[41] Chen WT et al. Distinct effects of Zn2+, Cu2+, Fe3+, and Al3+ on amyloid-beta stability, oligomerization, and aggregation: amyloid-beta destabilization promotes annular

[42] Bush AI et al. A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease. J Biol Chem 1993; 268(22):

[43] Duce JA et al. Iron-export ferroxidase activity of β-amyloid precursor protein is in‐

[44] Arispe N et al. Alzheimer disease amyloid ß protein forms calcium channels in bilay‐ er membranes: Blockade by tromethamine and aluminum. Proc Natl Acad Sci USA

[45] Arispe N et al. Zn2+ interactions with Alzheimer's amyloid ß protein calcium chan‐

[46] Kawahara M et al. Alzheimer's disease amyloid ß-protein forms Zn2+-sensitive, cati‐ on-selective channels across excised membrane patches from hypothalamic neurons.

[47] Kawahara M et al. Alzheimer's ß-amyloid, human islet amylin and prion protein fragment evoke intracellular free-calcium elevations by a common mechanism in a

[48] Kawahara M et al. Membrane incorporation, channel formation, and disruption of calcium homeostasis by Alzheimer's ß-amyloid protein, Int J Alzheimer Dis 2011; doi

[49] Diaz JC et al. Small molecule blockers of the Alzheimer Aß calcium channel potently protect neurons from Aß cytotoxicity. Proc Natl Acad Sci USA 2009;106(9):3348-53.

hypothalamic GnRH neuronal cell-line. J Biol Chem 2000; 275: 14077-14083.

protein in vitro, Biochem. Biophys. Res. Commun. 198: 531-535 (1994).

1994; 265: 1464-1467.

16109-12.

304583.

1993; 90: 567-571.

Biophys J 1997; 73: 67-75.

ties. Br J Pharmacol 2011; 163(2):211-9.

protofibril formation. J Biol Chem 2011; 286(11): 9646-56.

hibited by zinc in Alzheimer's disease. Cell 2010;142(6):857-67.

nels. Proc Natl Acad Sci USA 1996; 93: 1710-1715.

[36] Kawahara M et al. Aluminum promotes the aggregation of Alzheimer's amyroid ßprotein in vitro, Biochem. Biophys. Res. Commun. 198: 531-535 (1994).

[21] Kawahara M et al. Characterization of zinc-induced apoptosis of GT1-7 cells. Biomed

[22] Konoha K, Sadakane Y, Kawahara M. Effects of gadolinium and other metal on the neurotoxicity of immortalized hypothalamic neurons induced by zinc. Biomed Res

[23] Lee JY et al. Protection by pyruvate against transient forebrain ischemia in rats. J

[24] Sheline CT et al. Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J Neurosci 2000; 20:

[25] Sensi SL et al. Modulation of mitochondrial function by endogenous Zn2+ pools. Proc

[26] Konoha K, Sadakane Y, Kawahara M. Carnosine protects GT1-7 cells against zinc-in‐ duced neurotoxicity: a possible candidate for treatment for vascular type of demen‐

[27] Kawahara M et al. Protective substances against zinc-induced neuronal death after ischemia: carnosine a target for drug of vascular type of dementia. Recent Patents on

[28] Hipkiss AR. Carnosine and its possible roles in nutrition and health. Adv Food Nutr

[29] Corona C et al. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One

[30] Kawahara M et al. Zinc, copper, and carnosine attenuate neurotoxicity of prion frag‐

[31] Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron 1991; 6: 487-98.

problems on the road to therapeutics. Science 2002; 297: 353-6.

amyloid protein. Expert Rev Neurother 2009; 9: 681-93.

[32] Hardy J and Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and

[33] Kawahara M et al. Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-

[34] Fukuyama R et al. Age-dependent change in the levels of Aß40 and Aß42 in cerebro‐ spinal fluid from control subjects, and a decrease in the ratio of Aß42 to Aß40 level in cerebrospinal fluid from Alzheimer's disease patients. Eur Neurol 2000; 43:155-60.

[35] Kawahara M. Role of calcium dyshomeostasis via amyloid channels in the pathogen‐ esis of Alzheimer's disease. Current Pharmaceutical Design 2010; 16: 2779-2789.

Res Trace Elements 2002; 13: 280-281.

Trace Elements 2004; 15: 275-277.

 Trace Nutrient Res 2006; 23:1-8.

CNS Drug Discovery 2007; 2: 145-149.

ment PrP106-126. Metallomics 2011; 3: 726-734.

Res 2009; 57: 87-154.

2011; 6(3):e17971.

Neurosci 2001; 21: RC171.

3139-3146.

532 Neurodegenerative Diseases

**Chapter 22**

**Oligodendrocyte Metabolic Stress in**

**Neurodegeneration**

http://dx.doi.org/10.5772/54461

**1. Introduction**

a single class of drugs.

Daniel Radecki and Alexander Gow

Additional information is available at the end of the chapter

Neurodegeneration can be viewed in general terms as a common endpoint for a large and diverse group of nervous system diseases that arise in patients with disparate clinical symp‐ toms. As such, neurodegeneration is a convergent pathology wherein clinical signs are largely dependent on the location and identity of the degenerating cells. For example, in pa‐ tients for whom substantia nigra neurons are degenerating, the accompanying symptoms re‐ flect Parkinson disease (PD). Many of the symptoms are unique to PD, thereby enabling diagnosis, and would rarely be confused with those of patients suffering from amyotrophic lateral sclerosis (ALS), for whom ventral horn motor neurons in the spinal cord are lost. In the same vein, disease in patients with Alzheimer disease (AD) or multiple sclerosis (MS)

Despite these disease specific phenotypes, recent evidence indicates that their underlying pathophysiology, and that of many others, involves activation of a signaling pathway known as the unfolded protein response (UPR). This suggests the exciting possibility of a shared disease mechanism and, potentially, a common treatment strategy such as the use of

Research efforts from many laboratories have begun to elucidate the importance of the UPR to disease etiology. For example, causative mutations in familial forms of PD and AD are found in genes that encode components of protein aggregation and degradation pathways such as the ubiquitin-proteasome pathway, which strongly suggests that sporadic forms of these diseases also arise from perturbed protein folding or degradation [1-3]. In addition, the etiology of MS, which was once understood to be entirely caused by autoimmune at‐ tacks on the central nervous system (CNS), is becoming increasingly unclear because of new evidence pointing to an underlying degenerative pathology in oligodendrocytes that in‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Radecki and Gow; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

stem from the loss of distinct cell populations which confer unique phenotypes.

**Chapter 22**

### **Oligodendrocyte Metabolic Stress in Neurodegeneration**

Daniel Radecki and Alexander Gow

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54461

### **1. Introduction**

Neurodegeneration can be viewed in general terms as a common endpoint for a large and diverse group of nervous system diseases that arise in patients with disparate clinical symp‐ toms. As such, neurodegeneration is a convergent pathology wherein clinical signs are largely dependent on the location and identity of the degenerating cells. For example, in pa‐ tients for whom substantia nigra neurons are degenerating, the accompanying symptoms re‐ flect Parkinson disease (PD). Many of the symptoms are unique to PD, thereby enabling diagnosis, and would rarely be confused with those of patients suffering from amyotrophic lateral sclerosis (ALS), for whom ventral horn motor neurons in the spinal cord are lost. In the same vein, disease in patients with Alzheimer disease (AD) or multiple sclerosis (MS) stem from the loss of distinct cell populations which confer unique phenotypes.

Despite these disease specific phenotypes, recent evidence indicates that their underlying pathophysiology, and that of many others, involves activation of a signaling pathway known as the unfolded protein response (UPR). This suggests the exciting possibility of a shared disease mechanism and, potentially, a common treatment strategy such as the use of a single class of drugs.

Research efforts from many laboratories have begun to elucidate the importance of the UPR to disease etiology. For example, causative mutations in familial forms of PD and AD are found in genes that encode components of protein aggregation and degradation pathways such as the ubiquitin-proteasome pathway, which strongly suggests that sporadic forms of these diseases also arise from perturbed protein folding or degradation [1-3]. In addition, the etiology of MS, which was once understood to be entirely caused by autoimmune at‐ tacks on the central nervous system (CNS), is becoming increasingly unclear because of new evidence pointing to an underlying degenerative pathology in oligodendrocytes that in‐

© 2013 Radecki and Gow; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

volves UPR induction and secondary activation of the immune system. Finally, the etiology of oligodendrocyte metabolic diseases including at least two of the leukodystrophies, van‐ ishing white matter disease (VWM) and Pelizaeus-Merzbacher disease (PMD), is known to involve UPR activation.

ever, if the synthesis of these polypeptides surpasses the rate of degradation, they accumu‐

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

537

The importance of UPR signaling to cell homeostasis and survival is highlighted by the de‐ gree of conservation of this pathway in prokaryotes and in eukaryotes from yeast to mam‐ mals. Significant increases in signaling complexity in higher eukaryotes also indicates the growing importance of this pathway in multicellular organisms through evolution [13]. In most cases for eukaryotes, activation of the UPR by misfolded proteins causes rapid shut‐ down of global protein translation, expansion of intracellular membrane-bound compart‐ ments, induction of molecular chaperone expression and increased degradation of

In the event that such comprehensive changes in cell structure, reprogramming and metabo‐ lism are ineffective at curbing UPR signaling and reestablishing homeostasis, cells will in‐ evitably undergo apoptosis in a manner that limits damage to neighboring cells and the survival of the organism [14]. Surprisingly, the nature of the trigger that induces apoptosis appears to be divergent in different cell types, and several hypotheses have been developed

In general terms, the UPR signaling cascade maintains cell homeostasis, metabolism and cell survival [13, 15, 16]. In higher eukaryotes, the UPR can be divided into three path‐ ways named for the proteins that initiate signaling: IRE1α (inositol requiring protein 1α), ATF6 (activating transcription factor 6) and PERK (pancreatic endoplasmic reticulum kin‐ ase). Together, these pathways increase expression of molecular chaperone proteins, pro‐ tein degradation and decrease global translation to alleviate misfolding and restore

The IRE1α receptor is a transmembrane protein that is localized to the ER and detects the accumulation of misfolded proteins or, in more general terms, serves as a sensor of changes in secretory pathway protein flux. IRE1α was the first component of the UPR cascade to be identified in any eukaryote and is the only UPR sensor present in yeast [14, 18]. The ER lu‐ minal domain is topographically similar to the Major Histocompatibility Class (MHC) pro‐ teins of the immune system and appears to bind to the molecular chaperone protein, BiP, which maintains IRE1α as a monomer and prevents its activation. However, misfolded pro‐ tein accumulation in the ER lumen sequesters BiP from IRE1α and allows this receptor to homodimerize leading to transautophosphorylation and activation of its cytoplasmic endor‐

A major downstream target of the IRE1α nuclease domain is an mRNA that encodes the bzip transcription factor, X-box Binding Protein 1 (XBP1) [20]. Processing of this mRNA re‐ moves a short internal 26 base intron and completes the major open reading frame that enc‐ odes functional XBP1. The major target genes of XBP1 include molecular chaperones which

late in the ER, causing metabolic stress and induction of the UPR [12].

to explain the bulk of published studies as detailed below.

misfolded proteins.

**3.1. UPR signaling in mammals**

homeostasis. [12, 17].

*3.1.1. The IRE1 pathway*

ibonuclease P domain [19].

In this review, we begin with a general definition of normal versus disease states in terms of cell homeostasis and its relation to UPR signaling, metabolic stress and neurodegeneration. Next, we examine essential aspects of the UPR signaling cascade, as well as emerging con‐ cepts about UPR activation and function, and conclude with an examination of MS as a pri‐ mary UPR disease rather than its typical consideration as a primary autoimmune disease.

### **2. Metabolic stress and the concept of homeostasis**

An increasing awareness of the pathophysiology of neurodegeneration has led to the reali‐ zation that metabolic stress is a major contributor to disease etiology. This novel view can be conceptualized as follows. Cells under normal metabolic conditions are described as main‐ taining homeostasis. Metabolic stress is viewed as a loss of homeostasis, defined as any pathological process that impedes cell function.

Intracellular signaling pathways have evolved to detect and counteract many forms of meta‐ bolic stress. These pathways modify cell activity and impart significant protection under pathological conditions, thereby maintaining homeostasis. However, when metabolic stress disrupts homeostasis, cells become vulnerable to apoptosis leading to brain atrophy and dis‐ ease. These concepts have been principally developed to account for the pathophysiology and disease severity that we observe in animal models of PMD [4-7]. However, they are also relevant to other oligodendrocyte diseases as well as major neurological diseases like AD, PD and ALS.

### **3. Misfolded proteins trigger UPR signaling**

Two of the most important homeostatic features of normal cell function are the consistent and efficient translation of proteins and the post-translational folding and processing of those proteins into their stable higher-ordered conformations. However, not all protein mol‐ ecules achieve native conformations after translation even in normal cells, and particularly in genetic diseases when missense or nonsense mutations in coding exons of genes confer distinct misfolded conformations on the translated products [8, 9].

In cases of transmembrane or secreted proteins that are synthesized on the ER (endoplasmic reticulum) in eukaryotes, misfolded or abnormal folding intermediates are prevented from being transported beyond this compartment by the quality control machinery of the cell. These nascent polypeptide chains are either removed from the ER and degraded via the ubiquitin-proteasome system or are shunted into the lysosome by autophagy [10, 11]. How‐ ever, if the synthesis of these polypeptides surpasses the rate of degradation, they accumu‐ late in the ER, causing metabolic stress and induction of the UPR [12].

The importance of UPR signaling to cell homeostasis and survival is highlighted by the de‐ gree of conservation of this pathway in prokaryotes and in eukaryotes from yeast to mam‐ mals. Significant increases in signaling complexity in higher eukaryotes also indicates the growing importance of this pathway in multicellular organisms through evolution [13]. In most cases for eukaryotes, activation of the UPR by misfolded proteins causes rapid shut‐ down of global protein translation, expansion of intracellular membrane-bound compart‐ ments, induction of molecular chaperone expression and increased degradation of misfolded proteins.

In the event that such comprehensive changes in cell structure, reprogramming and metabo‐ lism are ineffective at curbing UPR signaling and reestablishing homeostasis, cells will in‐ evitably undergo apoptosis in a manner that limits damage to neighboring cells and the survival of the organism [14]. Surprisingly, the nature of the trigger that induces apoptosis appears to be divergent in different cell types, and several hypotheses have been developed to explain the bulk of published studies as detailed below.

#### **3.1. UPR signaling in mammals**

volves UPR induction and secondary activation of the immune system. Finally, the etiology of oligodendrocyte metabolic diseases including at least two of the leukodystrophies, van‐ ishing white matter disease (VWM) and Pelizaeus-Merzbacher disease (PMD), is known to

In this review, we begin with a general definition of normal versus disease states in terms of cell homeostasis and its relation to UPR signaling, metabolic stress and neurodegeneration. Next, we examine essential aspects of the UPR signaling cascade, as well as emerging con‐ cepts about UPR activation and function, and conclude with an examination of MS as a pri‐ mary UPR disease rather than its typical consideration as a primary autoimmune disease.

An increasing awareness of the pathophysiology of neurodegeneration has led to the reali‐ zation that metabolic stress is a major contributor to disease etiology. This novel view can be conceptualized as follows. Cells under normal metabolic conditions are described as main‐ taining homeostasis. Metabolic stress is viewed as a loss of homeostasis, defined as any

Intracellular signaling pathways have evolved to detect and counteract many forms of meta‐ bolic stress. These pathways modify cell activity and impart significant protection under pathological conditions, thereby maintaining homeostasis. However, when metabolic stress disrupts homeostasis, cells become vulnerable to apoptosis leading to brain atrophy and dis‐ ease. These concepts have been principally developed to account for the pathophysiology and disease severity that we observe in animal models of PMD [4-7]. However, they are also relevant to other oligodendrocyte diseases as well as major neurological diseases like AD,

Two of the most important homeostatic features of normal cell function are the consistent and efficient translation of proteins and the post-translational folding and processing of those proteins into their stable higher-ordered conformations. However, not all protein mol‐ ecules achieve native conformations after translation even in normal cells, and particularly in genetic diseases when missense or nonsense mutations in coding exons of genes confer

In cases of transmembrane or secreted proteins that are synthesized on the ER (endoplasmic reticulum) in eukaryotes, misfolded or abnormal folding intermediates are prevented from being transported beyond this compartment by the quality control machinery of the cell. These nascent polypeptide chains are either removed from the ER and degraded via the ubiquitin-proteasome system or are shunted into the lysosome by autophagy [10, 11]. How‐

**2. Metabolic stress and the concept of homeostasis**

pathological process that impedes cell function.

**3. Misfolded proteins trigger UPR signaling**

distinct misfolded conformations on the translated products [8, 9].

involve UPR activation.

536 Neurodegenerative Diseases

PD and ALS.

In general terms, the UPR signaling cascade maintains cell homeostasis, metabolism and cell survival [13, 15, 16]. In higher eukaryotes, the UPR can be divided into three path‐ ways named for the proteins that initiate signaling: IRE1α (inositol requiring protein 1α), ATF6 (activating transcription factor 6) and PERK (pancreatic endoplasmic reticulum kin‐ ase). Together, these pathways increase expression of molecular chaperone proteins, pro‐ tein degradation and decrease global translation to alleviate misfolding and restore homeostasis. [12, 17].

#### *3.1.1. The IRE1 pathway*

The IRE1α receptor is a transmembrane protein that is localized to the ER and detects the accumulation of misfolded proteins or, in more general terms, serves as a sensor of changes in secretory pathway protein flux. IRE1α was the first component of the UPR cascade to be identified in any eukaryote and is the only UPR sensor present in yeast [14, 18]. The ER lu‐ minal domain is topographically similar to the Major Histocompatibility Class (MHC) pro‐ teins of the immune system and appears to bind to the molecular chaperone protein, BiP, which maintains IRE1α as a monomer and prevents its activation. However, misfolded pro‐ tein accumulation in the ER lumen sequesters BiP from IRE1α and allows this receptor to homodimerize leading to transautophosphorylation and activation of its cytoplasmic endor‐ ibonuclease P domain [19].

A major downstream target of the IRE1α nuclease domain is an mRNA that encodes the bzip transcription factor, X-box Binding Protein 1 (XBP1) [20]. Processing of this mRNA re‐ moves a short internal 26 base intron and completes the major open reading frame that enc‐ odes functional XBP1. The major target genes of XBP1 include molecular chaperones which are ER-resident proteins that bind to unfolded or misfolded polypeptides [14]. Accordingly, the IRE1α pathway detects changes in protein flux and acts to increase the folding capacity of the ER, ultimately completing a negative feedback loop on the UPR.

lational changes that reduce the accumulation of misfolded polypeptides and ultimately negatively feedback to switch off the UPR. Collectively, these activities comprise the adaptive arm of the UPR cascade, which adjusts cell metabolism to maintain homeostasis and promote cell survival. However, the UPR cascade also appears to include a maladap‐ tive arm, the major function of which is to trigger apoptosis in the event that cells fail to

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

539

Although the maladaptive arm of the UPR is widely known and discussed in published studies, the molecular mechanisms underlying its activation are poorly understood. Many studies identify CHOP or a decoy kinase known as Tribbles3 (Trib3) as major components of the maladaptive trigger for apoptosis [23, 24]; however, this view reveals a significant co‐ nundrum. Thus, if PERK signaling requires CHOP expression to complete the negative feed‐ back loop that dephosphorylates eIF2α as part of the adaptive response, why would CHOP

There are three principal hypotheses that address this issue. The first proposes that CHOP is a molecular rheostat that drives distinct downstream pathways as a function of expression level [25, 26]. The second suggests that the IRE1 and PERK pathways act in concert to effect cell survival but drive apoptosis when the activities of these pathways are unbalanced [20]. The third hypothesizes that apoptosis is triggered stochastically at a restriction point in the PERK pathway, which is more-or-less coincident with the reinitiation of protein translation

Studies in human embryonic kidney 293 (HEK293) cells utilizing genetic and chemical in‐ duction of the UPR have led to the hypothesis of graded activation, mediated by CHOP, with apoptosis resulting from the highest levels of expression [25, 26]. Transient ER stress requires a UPR; however, the response itself would be modulated so that mild stress generates tapered transient CHOP induction, and severe prolonged stress causes sustained CHOP expression. Indeed, a modulated CHOP response has been observed during molecular and mechanical stress in vitro that activates PERK in the ER, with sus‐ tained PERK activation causing sustained CHOP expression and increased apoptosis. In contrast, oligodendrocytes undergoing severe metabolic stress and widespread apoptosis do not express CHOP, suggesting that its induction is transient even during severe stress

From their in vitro manipulation of the IRE1 and PERK pathways in HEK293 cells, Walter and colleagues [29] identified disparate roles for each pathway that could account for diver‐ gent UPR phenotypes in animal models of disease. The results showed that activating the PERK pathway alone decreased cell proliferation in vitro and triggered a morphological de‐ differentiation characterized by a loss of cell processes. In contrast, unilateral IRE1 activation increased cell numbers. Because activation of the PERK and IRE1 pathways stem from the

expression trigger apoptosis as part of the maladaptive response?

upon eIF2α dephosphorylation [17, 27].

*3.2.2. Balanced IRE1 and PERK signaling*

*3.2.1. CHOP as a rheostat*

[4, 6, 28].

maintain homeostasis.

#### *3.1.2. The ATF6 pathway*

A second UPR pathway is initiated through activation of the membrane-tethered ATF6 pro‐ tein and converges with IRE1α signaling. ATF6 interacts with BiP, similar to IRE1α. Misfold‐ ed proteins displace BiP from the ATF6 luminal domain and enable the protein to traffic from the ER to the Golgi apparatus where it is cleaved by the site 1 and site 2 proteases (S1P and S2P, respectively). The resulting cytosolic N-terminal fragment of ATF6 is the functional bzip transcription factor that heterodimerizes with XBP1 and induces expression of molecu‐ lar chaperone genes including BiP, glucose-regulated protein 94 (GRP94) and other genes encoding protein folding pathway proteins [15, 19]. ATF6 also upregulates proteins associat‐ ed with the ER Associated Degradation (ERAD) pathway, which is a checkpoint in the ER that ubiquitinates proteins and shuttles them into the cytoplasm for proteasome-mediated degradation [21]. Thus, ATF6 helps to upregulate chaperones to relieve mild protein mis‐ folding, but can also activate degradation of proteins that are severely misfolded and cannot be rescued by chaperones.

#### *3.1.3. The PERK pathway*

A third UPR pathway is regulated by an ER-resident receptor known as PERK. The luminal domain of PERK functions analogously to that of IRE1α in binding BiP, and is also activated by dimerization and transautophosphorylation. The cytoplasmic domain of PERK is a pro‐ tein kinase, a major target of which is the alpha subunit of eukaryotic initiation factor 2 (eIF2α). eIF2α is a critical component in ribosome assembly and can be inactivated by phos‐ phorylation, which leads to the shut down of global protein synthesis [17].

Despite global translation arrest, a small number of proteins that are critical to the UPR signal‐ ing are actively translated, including the bzip transcription factors, activating transcription fac‐ tor 4 (ATF4), ATF3 and the CCAAT-enhancer-binding protein homologous protein (CHOP) as well as the regulatory subunit of protein phosphatase 1 (PP1), known as growth-arrest and DNA damage protein 34 (GADD34) [17, 22]. The GADD34-PP1 complex is targeted to the ER membrane to dephosphorylate p-eIF2α and reinitiate protein translation. Thus, the PERK path‐ way temporarily halts protein synthesis to suppress additional accumulation of misfolded pro‐ teins in the ER. The pathway subsequently reactivates protein synthesis by opposing the phosphorylation activity of PERK. Thus, because of the time that is necessary to complete each of the steps downstream of eIF2α phosphorylation, the PERK pathway can be considered to be a time-delay circuit that forms a negative feedback loop to regulate UPR signaling.

#### **3.2. Adaptive and maladaptive facets of UPR signaling**

A common theme among the three branches of the UPR cascade is the similar activation of the ER-resident receptors by changes in protein flux leading to transcriptional or trans‐ lational changes that reduce the accumulation of misfolded polypeptides and ultimately negatively feedback to switch off the UPR. Collectively, these activities comprise the adaptive arm of the UPR cascade, which adjusts cell metabolism to maintain homeostasis and promote cell survival. However, the UPR cascade also appears to include a maladap‐ tive arm, the major function of which is to trigger apoptosis in the event that cells fail to maintain homeostasis.

Although the maladaptive arm of the UPR is widely known and discussed in published studies, the molecular mechanisms underlying its activation are poorly understood. Many studies identify CHOP or a decoy kinase known as Tribbles3 (Trib3) as major components of the maladaptive trigger for apoptosis [23, 24]; however, this view reveals a significant co‐ nundrum. Thus, if PERK signaling requires CHOP expression to complete the negative feed‐ back loop that dephosphorylates eIF2α as part of the adaptive response, why would CHOP expression trigger apoptosis as part of the maladaptive response?

There are three principal hypotheses that address this issue. The first proposes that CHOP is a molecular rheostat that drives distinct downstream pathways as a function of expression level [25, 26]. The second suggests that the IRE1 and PERK pathways act in concert to effect cell survival but drive apoptosis when the activities of these pathways are unbalanced [20]. The third hypothesizes that apoptosis is triggered stochastically at a restriction point in the PERK pathway, which is more-or-less coincident with the reinitiation of protein translation upon eIF2α dephosphorylation [17, 27].

#### *3.2.1. CHOP as a rheostat*

are ER-resident proteins that bind to unfolded or misfolded polypeptides [14]. Accordingly, the IRE1α pathway detects changes in protein flux and acts to increase the folding capacity

A second UPR pathway is initiated through activation of the membrane-tethered ATF6 pro‐ tein and converges with IRE1α signaling. ATF6 interacts with BiP, similar to IRE1α. Misfold‐ ed proteins displace BiP from the ATF6 luminal domain and enable the protein to traffic from the ER to the Golgi apparatus where it is cleaved by the site 1 and site 2 proteases (S1P and S2P, respectively). The resulting cytosolic N-terminal fragment of ATF6 is the functional bzip transcription factor that heterodimerizes with XBP1 and induces expression of molecu‐ lar chaperone genes including BiP, glucose-regulated protein 94 (GRP94) and other genes encoding protein folding pathway proteins [15, 19]. ATF6 also upregulates proteins associat‐ ed with the ER Associated Degradation (ERAD) pathway, which is a checkpoint in the ER that ubiquitinates proteins and shuttles them into the cytoplasm for proteasome-mediated degradation [21]. Thus, ATF6 helps to upregulate chaperones to relieve mild protein mis‐ folding, but can also activate degradation of proteins that are severely misfolded and cannot

A third UPR pathway is regulated by an ER-resident receptor known as PERK. The luminal domain of PERK functions analogously to that of IRE1α in binding BiP, and is also activated by dimerization and transautophosphorylation. The cytoplasmic domain of PERK is a pro‐ tein kinase, a major target of which is the alpha subunit of eukaryotic initiation factor 2 (eIF2α). eIF2α is a critical component in ribosome assembly and can be inactivated by phos‐

Despite global translation arrest, a small number of proteins that are critical to the UPR signal‐ ing are actively translated, including the bzip transcription factors, activating transcription fac‐ tor 4 (ATF4), ATF3 and the CCAAT-enhancer-binding protein homologous protein (CHOP) as well as the regulatory subunit of protein phosphatase 1 (PP1), known as growth-arrest and DNA damage protein 34 (GADD34) [17, 22]. The GADD34-PP1 complex is targeted to the ER membrane to dephosphorylate p-eIF2α and reinitiate protein translation. Thus, the PERK path‐ way temporarily halts protein synthesis to suppress additional accumulation of misfolded pro‐ teins in the ER. The pathway subsequently reactivates protein synthesis by opposing the phosphorylation activity of PERK. Thus, because of the time that is necessary to complete each of the steps downstream of eIF2α phosphorylation, the PERK pathway can be considered to be a

A common theme among the three branches of the UPR cascade is the similar activation of the ER-resident receptors by changes in protein flux leading to transcriptional or trans‐

phorylation, which leads to the shut down of global protein synthesis [17].

time-delay circuit that forms a negative feedback loop to regulate UPR signaling.

**3.2. Adaptive and maladaptive facets of UPR signaling**

of the ER, ultimately completing a negative feedback loop on the UPR.

*3.1.2. The ATF6 pathway*

538 Neurodegenerative Diseases

be rescued by chaperones.

*3.1.3. The PERK pathway*

Studies in human embryonic kidney 293 (HEK293) cells utilizing genetic and chemical in‐ duction of the UPR have led to the hypothesis of graded activation, mediated by CHOP, with apoptosis resulting from the highest levels of expression [25, 26]. Transient ER stress requires a UPR; however, the response itself would be modulated so that mild stress generates tapered transient CHOP induction, and severe prolonged stress causes sustained CHOP expression. Indeed, a modulated CHOP response has been observed during molecular and mechanical stress in vitro that activates PERK in the ER, with sus‐ tained PERK activation causing sustained CHOP expression and increased apoptosis. In contrast, oligodendrocytes undergoing severe metabolic stress and widespread apoptosis do not express CHOP, suggesting that its induction is transient even during severe stress [4, 6, 28].

#### *3.2.2. Balanced IRE1 and PERK signaling*

From their in vitro manipulation of the IRE1 and PERK pathways in HEK293 cells, Walter and colleagues [29] identified disparate roles for each pathway that could account for diver‐ gent UPR phenotypes in animal models of disease. The results showed that activating the PERK pathway alone decreased cell proliferation in vitro and triggered a morphological de‐ differentiation characterized by a loss of cell processes. In contrast, unilateral IRE1 activation increased cell numbers. Because activation of the PERK and IRE1 pathways stem from the accumulation of misfolded proteins, it is likely that the relative activation levels of these pathways generates a balance between proliferation and differentiation that determines the fate of the cells.

**4.1. Leukodystrophy and metabolic stress as a model of neurodegenerative disease**

consequences of this disease mechanism beyond the primary cell type involved.

Arguably, PMD is one of the most extensively characterized neurodegenerative UPR disease in terms of molecular and cellular etiology. In virtually all patients, disease stems from ge‐ netic lesions in the *X*-linked *Plp1* gene [44]. The gene products are polytopic membrane pro‐ teins that constitute approximately 50% of the total protein in the CNS myelin sheath and the developmental expression levels of this gene are among the most abundantly expressed

Mutations in the *Plp1* gene arises from three types of genetic lesions: duplications, deletions and missense/nonsense mutations. These lesions confer disease symptoms with a wide range of clinical severity that are mild in the case of deletions, severe in the case of duplica‐ tions and mild or severe for coding region mutations. In general, mild phenotypes are asso‐ ciated with reduced oligodendrocyte function but relatively little cell death while severe

Mild forms of disease caused by deletion of the entire *Plp1* gene or nonsense mutations in exon 1 are characterized by clinical presentation in middle age patients, often in the form of cognitive decline [43, 44] and a length-dependent dying back neuropathology. Although the absence of *Plp1* expression in patients does not significantly reduce oligodendrocyte func‐ tion and the amount of myelin formed during development, the absence of this protein re‐ duces the long-term stability of long myelinated tracts such as the corticospinal tract, which degenerate in later life. Importantly, the stability of the CNS specifically requires the PLP1 protein, and cannot be conferred by the alternatively-spliced PLP1 isoform, called DM-20,

forms cause widespread apoptosis and a virtual absence of white matter [45, 46].

which lacks a 35 amino acid segment in the cytoplasmic domain of the protein [47].

The leukodystrophies are a group of diseases characterized by a systemic absence of white matter in the CNS resulting in sensorimotor deficits, ataxia, hypotonia and eventual decline in cognitive function [36]. Although leukodystrophies affect all white matter tracts to vary‐ ing extents, they differ in their primary causes. For example, in the case of PMD the absence of white matter stems from mutations in the gene encoding the most abundant myelin pro‐ tein, proteolipid protein-1 (PLP1) [37-39], while VWM disease is caused by mutations in genes that encode subunits of the eIF2 complex [40]. In many cases, metabolic stress is se‐ vere enough that the disease develops in childhood and dramatically affects the life span of the patient [6, 38, 39, 41, 42]. The common mechanism between these leukodystrophies is the failure to manage and remove misfolded proteins, some of which rapidly activate the UPR leading to metabolic stress and apoptosis [38, 39]. Importantly, metabolic stress in oligoden‐ drocytes also leads to secondary neuron loss [43], which demonstrates the potentially severe

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

541

**etiology**

*4.1.1. Pelizaeus-Merzbacher disease*

*<IP_ADDRESS>. Gene duplications and deletions in PMD*

in mammals.

#### *3.2.3. Stochastic apoptosis*

The third hypothesis stems from the results of several in vivo studies involving CNS and PNS myelin mutant mice [17]. In contrast to in vitro studies in many cell types where CHOP expression drives apoptosis and CHOP loss-of-function promotes cell survival, ablation of the *Chop* gene in oligodendrocytes renders them much more susceptible to apoptosis under UPR conditions [6, 30]. Thus, CHOP promotes cell survival. In addition, induction of CHOP in Schwann cells does not induce cell death but, rather, causes dedifferentiation of these cells to promote their survival [27]. A similar mechanism is also observed in osteoblasts [31]. Together, these and other studies [29, 32] indicate that PERK signaling protects myelinating cells from apoptosis. If so, how do these cells undergo apoptosis?

One possibility is that myelinating cells become vulnerable to apoptosis at a restriction point in the PERK pathway as protein translation is restarted. At this restriction, the PP1-GADD34 complex dephosphorylates eIF2α and demand for ATP, GTP, NADH and other high-energy intermediates would dramatically increase. Sub-threshold levels of these critical molecules, perhaps also exacerbated by dissipation of the mitochondrial membrane potential, would occur stochastically in individual cells during translation-suppression and cause a loss of homeostasis leading to cell death. Under mild metabolic stress conditions, most cells would maintain supra-threshold levels of critical molecules and survive beyond the restriction point. Some of these cells would undergo apoptosis during subsequent UPR-induction cy‐ cles. Ultimately, the stronger the stress, the greater the number of UPR cycles, and the high‐ er the likelihood that cells would undergo apoptosis.

### **4. Oligodendrocyte metabolic stress and neurodegenerative disease**

Oligodendrocytes play a critical role in the CNS by myelinating axons to ensure efficient saltatory conduction and reliable communication between neurons over long distances as well as to promote neuronal survival [33]. The surface area of myelin membrane that is synthesized by each oligodendrocyte within a few days during development exceeds that of the cell body by several hundred fold, which makes oligodendrocytes one of the most metabolically active cell types [34]. Thus, it is not surprising that these cells are vulnera‐ ble to metabolic stress and undergo apoptosis associated with protein misfolding [4, 33, 35]. Genetic diseases that disrupt oligodendrocyte metabolism are associated with UPR signaling and are well characterized at the molecular level. It is also becoming increas‐ ingly clear that other diseases of oligodendrocytes, such as MS, involve this signaling pathway.

#### **4.1. Leukodystrophy and metabolic stress as a model of neurodegenerative disease etiology**

The leukodystrophies are a group of diseases characterized by a systemic absence of white matter in the CNS resulting in sensorimotor deficits, ataxia, hypotonia and eventual decline in cognitive function [36]. Although leukodystrophies affect all white matter tracts to vary‐ ing extents, they differ in their primary causes. For example, in the case of PMD the absence of white matter stems from mutations in the gene encoding the most abundant myelin pro‐ tein, proteolipid protein-1 (PLP1) [37-39], while VWM disease is caused by mutations in genes that encode subunits of the eIF2 complex [40]. In many cases, metabolic stress is se‐ vere enough that the disease develops in childhood and dramatically affects the life span of the patient [6, 38, 39, 41, 42]. The common mechanism between these leukodystrophies is the failure to manage and remove misfolded proteins, some of which rapidly activate the UPR leading to metabolic stress and apoptosis [38, 39]. Importantly, metabolic stress in oligoden‐ drocytes also leads to secondary neuron loss [43], which demonstrates the potentially severe consequences of this disease mechanism beyond the primary cell type involved.

#### *4.1.1. Pelizaeus-Merzbacher disease*

accumulation of misfolded proteins, it is likely that the relative activation levels of these pathways generates a balance between proliferation and differentiation that determines the

The third hypothesis stems from the results of several in vivo studies involving CNS and PNS myelin mutant mice [17]. In contrast to in vitro studies in many cell types where CHOP expression drives apoptosis and CHOP loss-of-function promotes cell survival, ablation of the *Chop* gene in oligodendrocytes renders them much more susceptible to apoptosis under UPR conditions [6, 30]. Thus, CHOP promotes cell survival. In addition, induction of CHOP in Schwann cells does not induce cell death but, rather, causes dedifferentiation of these cells to promote their survival [27]. A similar mechanism is also observed in osteoblasts [31]. Together, these and other studies [29, 32] indicate that PERK signaling protects myelinating

One possibility is that myelinating cells become vulnerable to apoptosis at a restriction point in the PERK pathway as protein translation is restarted. At this restriction, the PP1-GADD34 complex dephosphorylates eIF2α and demand for ATP, GTP, NADH and other high-energy intermediates would dramatically increase. Sub-threshold levels of these critical molecules, perhaps also exacerbated by dissipation of the mitochondrial membrane potential, would occur stochastically in individual cells during translation-suppression and cause a loss of homeostasis leading to cell death. Under mild metabolic stress conditions, most cells would maintain supra-threshold levels of critical molecules and survive beyond the restriction point. Some of these cells would undergo apoptosis during subsequent UPR-induction cy‐ cles. Ultimately, the stronger the stress, the greater the number of UPR cycles, and the high‐

**4. Oligodendrocyte metabolic stress and neurodegenerative disease**

Oligodendrocytes play a critical role in the CNS by myelinating axons to ensure efficient saltatory conduction and reliable communication between neurons over long distances as well as to promote neuronal survival [33]. The surface area of myelin membrane that is synthesized by each oligodendrocyte within a few days during development exceeds that of the cell body by several hundred fold, which makes oligodendrocytes one of the most metabolically active cell types [34]. Thus, it is not surprising that these cells are vulnera‐ ble to metabolic stress and undergo apoptosis associated with protein misfolding [4, 33, 35]. Genetic diseases that disrupt oligodendrocyte metabolism are associated with UPR signaling and are well characterized at the molecular level. It is also becoming increas‐ ingly clear that other diseases of oligodendrocytes, such as MS, involve this signaling

cells from apoptosis. If so, how do these cells undergo apoptosis?

er the likelihood that cells would undergo apoptosis.

fate of the cells.

540 Neurodegenerative Diseases

pathway.

*3.2.3. Stochastic apoptosis*

Arguably, PMD is one of the most extensively characterized neurodegenerative UPR disease in terms of molecular and cellular etiology. In virtually all patients, disease stems from ge‐ netic lesions in the *X*-linked *Plp1* gene [44]. The gene products are polytopic membrane pro‐ teins that constitute approximately 50% of the total protein in the CNS myelin sheath and the developmental expression levels of this gene are among the most abundantly expressed in mammals.

Mutations in the *Plp1* gene arises from three types of genetic lesions: duplications, deletions and missense/nonsense mutations. These lesions confer disease symptoms with a wide range of clinical severity that are mild in the case of deletions, severe in the case of duplica‐ tions and mild or severe for coding region mutations. In general, mild phenotypes are asso‐ ciated with reduced oligodendrocyte function but relatively little cell death while severe forms cause widespread apoptosis and a virtual absence of white matter [45, 46].

#### *<IP_ADDRESS>. Gene duplications and deletions in PMD*

Mild forms of disease caused by deletion of the entire *Plp1* gene or nonsense mutations in exon 1 are characterized by clinical presentation in middle age patients, often in the form of cognitive decline [43, 44] and a length-dependent dying back neuropathology. Although the absence of *Plp1* expression in patients does not significantly reduce oligodendrocyte func‐ tion and the amount of myelin formed during development, the absence of this protein re‐ duces the long-term stability of long myelinated tracts such as the corticospinal tract, which degenerate in later life. Importantly, the stability of the CNS specifically requires the PLP1 protein, and cannot be conferred by the alternatively-spliced PLP1 isoform, called DM-20, which lacks a 35 amino acid segment in the cytoplasmic domain of the protein [47].

In contrast, *Plp1* duplications cause severe phenotypes perinatally or within the first year of life. Children and adolescents with duplications exhibit severe cognitive decline in conjunc‐ tion with physical disabilities including loss of motor function and coordination [6, 48]. Be‐ cause of extremely high PLP1 expression levels during normal development, duplications may effectively overwhelm the secretory pathway in oligodendrocytes and disrupt cell func‐ tion or survival. Whether this disruption involves defective cholesterol trafficking [49] or immune activation [50] is currently unclear.

from *rsh* myelin sheaths, but DM-20 is present at normal levels[54]. This selective trafficking defect is consistent with the protein misfolding hypothesis [4, 5, 7, 51]. Oligodendrocyte metabolic stress leading to apoptosis is observed to occur at a moderate level in this strain

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

543

The *msd* mutation was originally described by Baumann and colleagues [65] and is charac‐ terized by an alanine to valine substitution at codon 243 (A243V) in PLP1 [66]. Mice harbor‐ ing this mutation exhibit severe symptoms, with behavioral changes evident by P13 and a short life span of 3 - 4 weeks. The amount of myelin in the *msd* CNS is severely reduced to approximately 5% of normal and the phenotype is very similar to that of *jimpy* mice on the same genetic background [62, 67]. Oligodendrocyte apoptosis is widespread in these mice and, similar to *rsh* mice, involves metabolic stress and activation of the UPR [4, 6, 12]. PMD patients with the corresponding mutation have a severe form of the disease with systemic

Importantly, some patients with severe forms of PMD such as those corresponding to the *msd* mutation also show signs of neuron loss as a consequence of profound hypomyelina‐ tion. These observations establish the principle that the survival of each of the major neural cell types is interdependent; thus, a primary insult in oligodendrocytes in the form of meta‐ bolic stress has secondary consequences for neurons [4, 6, 37]. Furthermore, symptoms in PMD can include autoimmune disease [68], which has major significance for the classifica‐ tion of MS as a neurodegenerative disease and suggests that the etiology may arise, at least in some instances, from primary metabolic stress in oligodendrocytes leading to secondary

Multiple sclerosis is the most common neurological disease in young adults worldwide and is typically described as an autoimmune attack on CNS white matter tracts resulting in focal lesions and degeneration of myelin throughout the CNS [69]. There are three major forms of this disease, relapse remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). RRMS is the most prevalent form and is characterized by patients for which lesions develop spontaneously and cause transient loss of neurological function (also known as a relapse) followed by essentially full recovery (known as remission). Dis‐ ease in RRMS patients eventually transitions from these transient symptoms to SPMS, when patients do not fully recover neurological function after relapses and sensorimotor deficits become more continuous and progressive. PPMS defines the third category, which is clini‐ cally similar to SPMS but without a preceding RRMS phase. Thus, patients experience rapid

Results from recent long-term clinical trials in RRMS patients that were medicated with any of several new immune suppressant therapies demonstrate that dramatic reductions in the number of new demyelinating lesions is accompanied by only modest amelioration of clini‐

**4.2. Is MS a neurodegenerative metabolic stress disease of oligodendrocytes?**

[6, 28] despite early claims to the contrary [64].

demyelination and widespread oligodendrocyte death.

*<IP_ADDRESS>. Severe disease in msd mice*

immune activation.

severe degeneration [69-71].

#### *<IP_ADDRESS>. Plp1 mutations in PMD*

Approximately 30% of PMD patients harbor mutations in the *Plp1* coding region that cause missense or nonsense changes in the protein primary structure. These changes arise throughout the coding region and cause a spectrum of disease severities in patients [43, 44]. Although there does not appear to be a correlation between the location of a mutation and disease severity, most mutations in the transmembrane domains cause severe disease. This is a general feature of membrane domain mutations in many secretory pathway proteins. Accordingly, the underlying cell biology of coding region mutations is proposed to stem from a failure of protein folding and trafficking through the secretory pathway, leading to metabolic stress and activation of the UPR [6, 12, 43, 44, 51]. Two missense mutations in PMD patients have also been identified in mice. Although similarities of disease symptoms and pathology conferred by each mutation might be anticipated because the PLP1 primary structure is identical in rodents and humans, the robustness of these findings provides a strong basis for using the animal models to model PMD [4, 52-55].

#### *4.1.2. Animal models of PMD*

A common goal in the analysis and development of therapeutic strategies to treat many neu‐ rodegenerative diseases is the generation of animal models, particularly in rodents which are amenable to genetic manipulation. Naturally-occurring animal models of PMD have been described in multiple species including dog, rabbit, rat and mouse [56-59], and engi‐ neered mutations have been generated in rats and mice [47, 52, 58, 60, 61].

The *jimpy* mouse, which exhibits a severe behavioral phenotype, is the original *Plp1* allele identified and has been characterized in greatest detail [57]. More recently, the *rumpshaker* (*rsh*) and *myelin synthesis-deficient* (*msd*) alleles have become popular not only because they exhibit mild and severe phenotypes, respectively, but also because the specific single amino acid changes harbored by these strains are also found in humans [54, 62].

#### *<IP_ADDRESS>. Mild disease in rsh mice*

This allele was originally described by Griffiths and colleagues and harbors an isoleucine to threonine mutation at codon 187 (I187T) in the second extracellular domain of PLP1 [54, 63]. These mice are fertile and exhibit a normal life span with behavioral changes becoming evi‐ dent between 13 – 19 days after birth (P13 – 19), depending on the background strain of the colony. The total myelin content of the brain is reduced to 40–50%. PLP1 is virtually absent from *rsh* myelin sheaths, but DM-20 is present at normal levels[54]. This selective trafficking defect is consistent with the protein misfolding hypothesis [4, 5, 7, 51]. Oligodendrocyte metabolic stress leading to apoptosis is observed to occur at a moderate level in this strain [6, 28] despite early claims to the contrary [64].

#### *<IP_ADDRESS>. Severe disease in msd mice*

In contrast, *Plp1* duplications cause severe phenotypes perinatally or within the first year of life. Children and adolescents with duplications exhibit severe cognitive decline in conjunc‐ tion with physical disabilities including loss of motor function and coordination [6, 48]. Be‐ cause of extremely high PLP1 expression levels during normal development, duplications may effectively overwhelm the secretory pathway in oligodendrocytes and disrupt cell func‐ tion or survival. Whether this disruption involves defective cholesterol trafficking [49] or

Approximately 30% of PMD patients harbor mutations in the *Plp1* coding region that cause missense or nonsense changes in the protein primary structure. These changes arise throughout the coding region and cause a spectrum of disease severities in patients [43, 44]. Although there does not appear to be a correlation between the location of a mutation and disease severity, most mutations in the transmembrane domains cause severe disease. This is a general feature of membrane domain mutations in many secretory pathway proteins. Accordingly, the underlying cell biology of coding region mutations is proposed to stem from a failure of protein folding and trafficking through the secretory pathway, leading to metabolic stress and activation of the UPR [6, 12, 43, 44, 51]. Two missense mutations in PMD patients have also been identified in mice. Although similarities of disease symptoms and pathology conferred by each mutation might be anticipated because the PLP1 primary structure is identical in rodents and humans, the robustness of these findings provides a

A common goal in the analysis and development of therapeutic strategies to treat many neu‐ rodegenerative diseases is the generation of animal models, particularly in rodents which are amenable to genetic manipulation. Naturally-occurring animal models of PMD have been described in multiple species including dog, rabbit, rat and mouse [56-59], and engi‐

The *jimpy* mouse, which exhibits a severe behavioral phenotype, is the original *Plp1* allele identified and has been characterized in greatest detail [57]. More recently, the *rumpshaker* (*rsh*) and *myelin synthesis-deficient* (*msd*) alleles have become popular not only because they exhibit mild and severe phenotypes, respectively, but also because the specific single amino

This allele was originally described by Griffiths and colleagues and harbors an isoleucine to threonine mutation at codon 187 (I187T) in the second extracellular domain of PLP1 [54, 63]. These mice are fertile and exhibit a normal life span with behavioral changes becoming evi‐ dent between 13 – 19 days after birth (P13 – 19), depending on the background strain of the colony. The total myelin content of the brain is reduced to 40–50%. PLP1 is virtually absent

strong basis for using the animal models to model PMD [4, 52-55].

neered mutations have been generated in rats and mice [47, 52, 58, 60, 61].

acid changes harbored by these strains are also found in humans [54, 62].

immune activation [50] is currently unclear.

*<IP_ADDRESS>. Plp1 mutations in PMD*

542 Neurodegenerative Diseases

*4.1.2. Animal models of PMD*

*<IP_ADDRESS>. Mild disease in rsh mice*

The *msd* mutation was originally described by Baumann and colleagues [65] and is charac‐ terized by an alanine to valine substitution at codon 243 (A243V) in PLP1 [66]. Mice harbor‐ ing this mutation exhibit severe symptoms, with behavioral changes evident by P13 and a short life span of 3 - 4 weeks. The amount of myelin in the *msd* CNS is severely reduced to approximately 5% of normal and the phenotype is very similar to that of *jimpy* mice on the same genetic background [62, 67]. Oligodendrocyte apoptosis is widespread in these mice and, similar to *rsh* mice, involves metabolic stress and activation of the UPR [4, 6, 12]. PMD patients with the corresponding mutation have a severe form of the disease with systemic demyelination and widespread oligodendrocyte death.

Importantly, some patients with severe forms of PMD such as those corresponding to the *msd* mutation also show signs of neuron loss as a consequence of profound hypomyelina‐ tion. These observations establish the principle that the survival of each of the major neural cell types is interdependent; thus, a primary insult in oligodendrocytes in the form of meta‐ bolic stress has secondary consequences for neurons [4, 6, 37]. Furthermore, symptoms in PMD can include autoimmune disease [68], which has major significance for the classifica‐ tion of MS as a neurodegenerative disease and suggests that the etiology may arise, at least in some instances, from primary metabolic stress in oligodendrocytes leading to secondary immune activation.

#### **4.2. Is MS a neurodegenerative metabolic stress disease of oligodendrocytes?**

Multiple sclerosis is the most common neurological disease in young adults worldwide and is typically described as an autoimmune attack on CNS white matter tracts resulting in focal lesions and degeneration of myelin throughout the CNS [69]. There are three major forms of this disease, relapse remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). RRMS is the most prevalent form and is characterized by patients for which lesions develop spontaneously and cause transient loss of neurological function (also known as a relapse) followed by essentially full recovery (known as remission). Dis‐ ease in RRMS patients eventually transitions from these transient symptoms to SPMS, when patients do not fully recover neurological function after relapses and sensorimotor deficits become more continuous and progressive. PPMS defines the third category, which is clini‐ cally similar to SPMS but without a preceding RRMS phase. Thus, patients experience rapid severe degeneration [69-71].

Results from recent long-term clinical trials in RRMS patients that were medicated with any of several new immune suppressant therapies demonstrate that dramatic reductions in the number of new demyelinating lesions is accompanied by only modest amelioration of clini‐ cal symptoms [72-75]. Moreover, patients continue to experience disease progression. These data indicate that the number of autoimmune attacks on the CNS is not strongly correlated with increasing disease severity and that there may be additional unknown mechanisms in‐ volved in the pathogenesis. If so, then immune attacks may actually be secondary to an un‐ derlying primary etiology.

proinflammatory cytokine release [79, 91-93]. However, these models have significant shortcomings in modeling MS pathology. For example, the neurological phenotypes in affected mice largely stems from tissue edema rather than demyelination. Although some models generate immune mediated demyelination, symptoms are monophasic rather than multiphasic and relapsing-remitting, in contrast to the most common form of MS [94]. Finally, in the absence of gray matter lesions and subsequent neuronal degenera‐ tion, these models fail to recapitulate the most debilitating features of MS that contribute

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

545

To overcome such shortcomings, we have developed a novel genetic mouse model of MS pathology that is based on primary metabolic stress in oligodendrocytes [95]. The etiology of disease in these mice has been characterized in mechanistic detail [4-7, 51] and we are cur‐ rently determining if we can recapitulate the degenerative white and gray matter lesions that arise in MS patients without specifically provoking the immune system to attack the CNS. Furthermore, we are determining if our primary insult in oligodendrocytes can secon‐ darily induce a relapsing-remitting or progressive autoimmune phenotype in the mice that would account for the pathophysiology observed in MS patients in terms of metabolic stress

**5. Identifying metabolic stress for the diagnosis of neurodegenerative**

For many neurodegenerative diseases, progress toward finding treatments and cures is painstakingly slow. This is in part limited by current capabilities for real-time imaging of the CNS as well as by ethical constraints that protect the health of patients and often exclude invasive procedures such as biopsies. These limitations largely confine research studies to post-mortem tissue, or generating in vitro and in vivo animal models, to develop treatments for disease. In many cases, these approaches have proved only partially effective for the

Recently, several imaging technologies have advanced significantly and become sufficiently widespread in hospitals for routine application to neurodegenerative diseases like AD and MS, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS),

Magnetic resonance techniques are widely used in clinical diagnostics of many diseases since their development approximately 40 years ago [86, 101]. Nevertheless, there are signif‐ icant drawbacks for their use in neurodegenerative diseases, particularly with respect to ear‐ ly disease detection [69, 102]. MRI is the most common technique used, and is particularly important for identifying white matter pathology such as hypomyelination or demyelinat‐ ing lesions, as well as gray matter degeneration, because it can easily detect differences in

to the declining quality of life for patients [77].

rather than primary autoimmune activation.

study of neurodegenerative diseases [79, 94, 96, 97].

and positron emission tomography (PET) [98-100].

**5.1. Magnetic resonance imaging**

**diseases**

Clues about the nature of such an unknown etiology in MS are scarce, but may be found in the clinical literature. For example, a few case reports detailing the misdiagnosis of PMD as childhood MS indicate that the symptoms of these two diseases overlap significantly. In‐ deed, the responsiveness of one of these patients to steroids suggests that PMD symptoms can be exacerbated by immune system activation at some level and perhaps similar to MS. Together, these reports provide tantalizing, if anecdotal, evidence that metabolic stress in oligodendrocytes could be one form of a primary etiology that secondarily activates the im‐ mune system [76-78].

#### *4.2.1. Neurodegeneration in MS*

The immune demyelinating lesion in white matter is an important component of MS pathol‐ ogy that has been studied extensively [76, 79-81]. However, a plethora of the clinical symp‐ toms, particularly those affecting the daily activities of patients and significantly reducing their quality of life, stem from axonal transection and loss of neurons in gray matter regions [82]. The significance of this degenerative feature is that emergent immune suppressive therapies might not be expected to have a major impact in halting symptom progression [81, 83, 84]. Cognitive decline, memory loss, partial paralysis, and optic neuritis are caused by the loss of neurons in different brain regions that are spared from direct immune attacks but still contribute to disease, especially for the more severe SPMS and PPMS forms [78, 85].

Gray matter cortical atrophy may constitute the majority of the total tissue atrophy observed in MS patients, especially those with SPMS and PPMS [86-88]. Although this pathological feature has been known for decades, one of the most important advances contributing to our understanding and acceptance of neuron loss as a major, if not the principal, symptom of MS is the increasing sensitivity for detecting gray matter lesions using clinical diagnostic MRIs. Thus, with renewed interest and appreciation for this issue, there is an urgent need to understand the underlying pathogenesis. In this regard, the development of novel animal models will lead to new hypotheses and the development of novel therapeutic strategies.

#### *4.2.2. Current and future MS models*

Because of the characterization of MS as a primary autoimmune disease, a large propor‐ tion of animal model studies, particularly in mice, have focused on developing and char‐ acterizing immune models such as experimental autoimmune encephalomyelitis (EAE) [79, 81, 89, 90]. These models rely on priming the peripheral immune system with inject‐ ed peptides from various myelin proteins to stimulate the immune system to attack and demyelinate white matter tracts. Damage is largely confined to spinal cord and is charac‐ terized by immune cell profiles of CD4+ , CD8+ T-cells and CD68+ macrophages as well as proinflammatory cytokine release [79, 91-93]. However, these models have significant shortcomings in modeling MS pathology. For example, the neurological phenotypes in affected mice largely stems from tissue edema rather than demyelination. Although some models generate immune mediated demyelination, symptoms are monophasic rather than multiphasic and relapsing-remitting, in contrast to the most common form of MS [94]. Finally, in the absence of gray matter lesions and subsequent neuronal degenera‐ tion, these models fail to recapitulate the most debilitating features of MS that contribute to the declining quality of life for patients [77].

To overcome such shortcomings, we have developed a novel genetic mouse model of MS pathology that is based on primary metabolic stress in oligodendrocytes [95]. The etiology of disease in these mice has been characterized in mechanistic detail [4-7, 51] and we are cur‐ rently determining if we can recapitulate the degenerative white and gray matter lesions that arise in MS patients without specifically provoking the immune system to attack the CNS. Furthermore, we are determining if our primary insult in oligodendrocytes can secon‐ darily induce a relapsing-remitting or progressive autoimmune phenotype in the mice that would account for the pathophysiology observed in MS patients in terms of metabolic stress rather than primary autoimmune activation.

### **5. Identifying metabolic stress for the diagnosis of neurodegenerative diseases**

For many neurodegenerative diseases, progress toward finding treatments and cures is painstakingly slow. This is in part limited by current capabilities for real-time imaging of the CNS as well as by ethical constraints that protect the health of patients and often exclude invasive procedures such as biopsies. These limitations largely confine research studies to post-mortem tissue, or generating in vitro and in vivo animal models, to develop treatments for disease. In many cases, these approaches have proved only partially effective for the study of neurodegenerative diseases [79, 94, 96, 97].

Recently, several imaging technologies have advanced significantly and become sufficiently widespread in hospitals for routine application to neurodegenerative diseases like AD and MS, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) [98-100].

#### **5.1. Magnetic resonance imaging**

cal symptoms [72-75]. Moreover, patients continue to experience disease progression. These data indicate that the number of autoimmune attacks on the CNS is not strongly correlated with increasing disease severity and that there may be additional unknown mechanisms in‐ volved in the pathogenesis. If so, then immune attacks may actually be secondary to an un‐

Clues about the nature of such an unknown etiology in MS are scarce, but may be found in the clinical literature. For example, a few case reports detailing the misdiagnosis of PMD as childhood MS indicate that the symptoms of these two diseases overlap significantly. In‐ deed, the responsiveness of one of these patients to steroids suggests that PMD symptoms can be exacerbated by immune system activation at some level and perhaps similar to MS. Together, these reports provide tantalizing, if anecdotal, evidence that metabolic stress in oligodendrocytes could be one form of a primary etiology that secondarily activates the im‐

The immune demyelinating lesion in white matter is an important component of MS pathol‐ ogy that has been studied extensively [76, 79-81]. However, a plethora of the clinical symp‐ toms, particularly those affecting the daily activities of patients and significantly reducing their quality of life, stem from axonal transection and loss of neurons in gray matter regions [82]. The significance of this degenerative feature is that emergent immune suppressive therapies might not be expected to have a major impact in halting symptom progression [81, 83, 84]. Cognitive decline, memory loss, partial paralysis, and optic neuritis are caused by the loss of neurons in different brain regions that are spared from direct immune attacks but still contribute to disease, especially for the more severe SPMS and PPMS forms [78, 85].

Gray matter cortical atrophy may constitute the majority of the total tissue atrophy observed in MS patients, especially those with SPMS and PPMS [86-88]. Although this pathological feature has been known for decades, one of the most important advances contributing to our understanding and acceptance of neuron loss as a major, if not the principal, symptom of MS is the increasing sensitivity for detecting gray matter lesions using clinical diagnostic MRIs. Thus, with renewed interest and appreciation for this issue, there is an urgent need to understand the underlying pathogenesis. In this regard, the development of novel animal models will lead to new hypotheses and the development of novel therapeutic strategies.

Because of the characterization of MS as a primary autoimmune disease, a large propor‐ tion of animal model studies, particularly in mice, have focused on developing and char‐ acterizing immune models such as experimental autoimmune encephalomyelitis (EAE) [79, 81, 89, 90]. These models rely on priming the peripheral immune system with inject‐ ed peptides from various myelin proteins to stimulate the immune system to attack and demyelinate white matter tracts. Damage is largely confined to spinal cord and is charac‐

, CD8+ T-cells and CD68+ macrophages as well as

derlying primary etiology.

544 Neurodegenerative Diseases

mune system [76-78].

*4.2.1. Neurodegeneration in MS*

*4.2.2. Current and future MS models*

terized by immune cell profiles of CD4+

Magnetic resonance techniques are widely used in clinical diagnostics of many diseases since their development approximately 40 years ago [86, 101]. Nevertheless, there are signif‐ icant drawbacks for their use in neurodegenerative diseases, particularly with respect to ear‐ ly disease detection [69, 102]. MRI is the most common technique used, and is particularly important for identifying white matter pathology such as hypomyelination or demyelinat‐ ing lesions, as well as gray matter degeneration, because it can easily detect differences in tissue structure or composition between normal and diseased regions. Applications to ex‐ pand the utility of this technique beyond the structural realm include injectable biomarkers to detect subclinical disease or to follow the evolution of lesions in real time, but these are currently nonexistent except for animal studies [103].

The lessons learned from PMD and other neurodegenerative diseases could be relevant to MS and may help to explain why this disease is recalcitrant to treatments that only target the immunological aspects of the pathophysiology. Thus, considering MS as a gain-of-func‐ tion disease with an underlying condition of unknown etiology that is exacerbated by auto‐ immune activation may shed new light on the pathophysiology and lead to novel

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

547

Although neurodegenerative diseases have typically been defined as a disparate group of diseases involving neurons, there is clear evidence in the clinical and basic science literature against such a narrow viewpoint. For example, diseases of the white matter such as PMD and MS arise from primary insults to oligodendrocytes and cause neuron loss in gray matter and lead to behavioral changes and memory loss. This reflects a broader consideration that all major cell types of the CNS are interdependent and degenerative changes in one of these

In similar vein, the fundamental belief by immunologists that MS is a primary autoimmune disease is no longer tenable. Clear evidence from large clinical trials demonstrates that the elimination of adaptive immune cells from the CNS by various forms of immune suppres‐ sion does not halt the progression of disease at early or late stages. The simplest interpreta‐ tion of these data is that there is an underlying etiology that is poorly understood and must be recognized. In light of overlapping symptoms between PMD and MS, it is plausible that metabolic stress could play a primary role in oligodendrocyte degeneration with secondary activation of immune cells. Indeed, several studies have demonstrated induction of the UPR

UPR (unfolded protein response), IRE (inositol requiring protein), PERK (pancreatic endo‐ plasmic reticulum kinase), ATF (activating transcription factor), XBP (X-box binding pro‐ tein), CHOP (CCAAT/-enhancer binding protein homologous protein), PLP1 (proteolipid protein-1), GADD34 (growth arrest and DNA damage protein 34), BiP (chaperone protein), eIF2α (eukaryotic initiation factor 2 α), PP1 (protein phosphatase 1), GRP94 (glucose-regu‐ lated protein 94), S1P (site 1 protease), S2P (site 2 protease), ERAD (endoplasmic reticulum associated degradation), ataxia (lack of voluntary muscle coordination), hypotonia (low muscle tone), RRMS (relapse-remitting Multiple Sclerosis), SPMS (secondary progressive Multiple Sclerosis), PPMS (primary progressive Multiple Sclerosis), CD4,8,68 (cluster of dif‐ ferentiation, immune cell specific glycoproteins), *rumpshaker* mutation (*rsh*), *myelin-synthesis deficient* mutation (*msd*), MRI (magnetic resonance imaging), MRS (magnetic resonance spec‐

therapeutic strategies to ameliorate the symptoms [70, 108, 109].

will lead to loss of at least some of the other cell types.

troscopy), PET (positron emission tomography).

**7. Conclusion**

in MS tissue.

**Nomenclature**

The imaging of metabolic changes in structurally normal regions of the CNS can be achieved using MRS [100, 104], but this technology is currently limited to a few major neurochemicals at low resolution. MRS can be used to detect neuron cell loss by monitoring levels of the neurochemical, N-acetyl aspartate (NAA), which is specific to this cell type [99]. However, the time, expense and difficulty of scanning more than one region of the CNS at a time se‐ verely limits the use of MRS for early disease detection when clinicians are uncertain about the specific location of lesions.

#### **5.2. Positron emission tomography**

Positron emission tomography involves the incorporation of radioactive molecules into me‐ tabolites that are selectively taken up by defined cell populations so that their location and metabolic activity can be analyzed [105]. This technique has the potential to generate de‐ tailed information about the molecular basis of neurodegeneration because the metabolism of affected cells changes dramatically as they lose homeostasis. PET has been used success‐ fully in diseases such as AD and PD where degeneration of specific neuronal populations can be monitored *in vivo* even before patients experience significant symptoms [106]. How‐ ever, a significant drawback with this technique is its low resolution, which renders the technique very limited for small animal model studies.

### **6. Treatments for metabolic stress in neurodegenerative diseases**

Increasing awareness and more sophisticated technologies have enabled earlier detection of neurodegenerative processes. However, the development of treatment strategies often has been hampered, in large measure because of the enormous plasticity of the CNS which enables neuronal circuits to compensate for ongoing damage and cell loss. Thus, these diseases only become clinically apparent at advanced stages when damage is wide‐ spread and irreparable.

The treatment of neurodegenerative diseases is also hampered by the fact that a number of these diseases stem from toxic gain-of-function, rather than loss-of-function, phenotypes. For example, deletion of the *Plp1* gene is the most mild form of PMD; thus, the loss of the protein in myelin does not confer a strong phenotype. However, mutations that cause PLP1 to misfold are toxic to oligodendrocytes because of the extremely rapid accumulation of the intermediates in the ER, which overwhelm the capacity of the UPR to eliminate them through the ubiquitin-proteasome system [107]. Therapeutic strategies to insert a wild type *Plp1* allele into these patients would fail unless the toxic protein from the mutant allele were also eliminated.

The lessons learned from PMD and other neurodegenerative diseases could be relevant to MS and may help to explain why this disease is recalcitrant to treatments that only target the immunological aspects of the pathophysiology. Thus, considering MS as a gain-of-func‐ tion disease with an underlying condition of unknown etiology that is exacerbated by auto‐ immune activation may shed new light on the pathophysiology and lead to novel therapeutic strategies to ameliorate the symptoms [70, 108, 109].

### **7. Conclusion**

tissue structure or composition between normal and diseased regions. Applications to ex‐ pand the utility of this technique beyond the structural realm include injectable biomarkers to detect subclinical disease or to follow the evolution of lesions in real time, but these are

The imaging of metabolic changes in structurally normal regions of the CNS can be achieved using MRS [100, 104], but this technology is currently limited to a few major neurochemicals at low resolution. MRS can be used to detect neuron cell loss by monitoring levels of the neurochemical, N-acetyl aspartate (NAA), which is specific to this cell type [99]. However, the time, expense and difficulty of scanning more than one region of the CNS at a time se‐ verely limits the use of MRS for early disease detection when clinicians are uncertain about

Positron emission tomography involves the incorporation of radioactive molecules into me‐ tabolites that are selectively taken up by defined cell populations so that their location and metabolic activity can be analyzed [105]. This technique has the potential to generate de‐ tailed information about the molecular basis of neurodegeneration because the metabolism of affected cells changes dramatically as they lose homeostasis. PET has been used success‐ fully in diseases such as AD and PD where degeneration of specific neuronal populations can be monitored *in vivo* even before patients experience significant symptoms [106]. How‐ ever, a significant drawback with this technique is its low resolution, which renders the

**6. Treatments for metabolic stress in neurodegenerative diseases**

Increasing awareness and more sophisticated technologies have enabled earlier detection of neurodegenerative processes. However, the development of treatment strategies often has been hampered, in large measure because of the enormous plasticity of the CNS which enables neuronal circuits to compensate for ongoing damage and cell loss. Thus, these diseases only become clinically apparent at advanced stages when damage is wide‐

The treatment of neurodegenerative diseases is also hampered by the fact that a number of these diseases stem from toxic gain-of-function, rather than loss-of-function, phenotypes. For example, deletion of the *Plp1* gene is the most mild form of PMD; thus, the loss of the protein in myelin does not confer a strong phenotype. However, mutations that cause PLP1 to misfold are toxic to oligodendrocytes because of the extremely rapid accumulation of the intermediates in the ER, which overwhelm the capacity of the UPR to eliminate them through the ubiquitin-proteasome system [107]. Therapeutic strategies to insert a wild type *Plp1* allele into these patients would fail unless the toxic protein from the mutant allele were

currently nonexistent except for animal studies [103].

technique very limited for small animal model studies.

the specific location of lesions.

546 Neurodegenerative Diseases

spread and irreparable.

also eliminated.

**5.2. Positron emission tomography**

Although neurodegenerative diseases have typically been defined as a disparate group of diseases involving neurons, there is clear evidence in the clinical and basic science literature against such a narrow viewpoint. For example, diseases of the white matter such as PMD and MS arise from primary insults to oligodendrocytes and cause neuron loss in gray matter and lead to behavioral changes and memory loss. This reflects a broader consideration that all major cell types of the CNS are interdependent and degenerative changes in one of these will lead to loss of at least some of the other cell types.

In similar vein, the fundamental belief by immunologists that MS is a primary autoimmune disease is no longer tenable. Clear evidence from large clinical trials demonstrates that the elimination of adaptive immune cells from the CNS by various forms of immune suppres‐ sion does not halt the progression of disease at early or late stages. The simplest interpreta‐ tion of these data is that there is an underlying etiology that is poorly understood and must be recognized. In light of overlapping symptoms between PMD and MS, it is plausible that metabolic stress could play a primary role in oligodendrocyte degeneration with secondary activation of immune cells. Indeed, several studies have demonstrated induction of the UPR in MS tissue.

### **Nomenclature**

UPR (unfolded protein response), IRE (inositol requiring protein), PERK (pancreatic endo‐ plasmic reticulum kinase), ATF (activating transcription factor), XBP (X-box binding pro‐ tein), CHOP (CCAAT/-enhancer binding protein homologous protein), PLP1 (proteolipid protein-1), GADD34 (growth arrest and DNA damage protein 34), BiP (chaperone protein), eIF2α (eukaryotic initiation factor 2 α), PP1 (protein phosphatase 1), GRP94 (glucose-regu‐ lated protein 94), S1P (site 1 protease), S2P (site 2 protease), ERAD (endoplasmic reticulum associated degradation), ataxia (lack of voluntary muscle coordination), hypotonia (low muscle tone), RRMS (relapse-remitting Multiple Sclerosis), SPMS (secondary progressive Multiple Sclerosis), PPMS (primary progressive Multiple Sclerosis), CD4,8,68 (cluster of dif‐ ferentiation, immune cell specific glycoproteins), *rumpshaker* mutation (*rsh*), *myelin-synthesis deficient* mutation (*msd*), MRI (magnetic resonance imaging), MRS (magnetic resonance spec‐ troscopy), PET (positron emission tomography).

### **Acknowledgements**

This work was supported by grants to A.G. from the National Institutes of Health, NINDS, NS067157 and the National Multiple Sclerosis Society, RG4078 and RG4639.

[7] Gow A, Lazzarini R. A cellular mechanism governing the severity of Pelizaeus

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

549

[8] Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJM, Samali A. Unfolded pro‐ teins and endoplasmic reticulum stress in neurodegenerative disorders. Journal of

[9] Tosic M, Matthey B, Gow A, Lazzarini RA, Matthieu JM. Intracellular transport of the DM-20 bearing shaking pup (shp) mutation and its possible phenotypic conse‐

[10] Scheper W, Nijholt DAT, Hoozemans JJM. The unfolded protein response and pro‐ teostasis in Alzheimer disease: Preferential activation of autophagy by endoplasmic

[11] Yu Z, Wang AM, Adachi H, Katsuno M, Sobue G, Yue Z, Robins DM, Lieberman AP. Macroautophagy Is Regulated by the UPR–Mediator CHOP and Accentuates the

[12] Gow A, Sharma R. The unfolded protein response in protein aggregating diseases.

[13] Mori K. Signalling Pathways in the Unfolded Protein Response: Development from

[14] Zhang K, Kaufman RJ. The unfolded protein response. Neurology 2006;66(1 suppl 1):

[15] Walter P, Ron D. The Unfolded Protein Response: From Stress Pathway to Homeo‐

[16] Ye C, Verchot J. Role of unfolded protein response in plant virus infection. Plant Sig‐

[17] Gow A, Wrabetz L. CHOP and the endoplasmic reticulum stress response in myeli‐

[18] Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress

[19] Cao S, Kaufman R. Unfolded protein response. Current Biology 2012;22(16): R622-

[20] Gardner BM, Walter P. Unfolded Proteins Are Ire1-Activating Ligands That Directly Induce the Unfolded Protein Response. Science 2011;333(6051): 1891-1894.

[21] Egawa N, Yamamoto K, Inoue H, Hikawa R, Nishi K, Mori K, Takahashi R. The En‐ doplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death. Journal of Biological Chemistry 2011;286(10):

−Merzbacher disease. Nature Genetics 1996;13: 422-428.

Cellular and Molecular Medicine 2011;15(10): 2025-2039.

reticulum stress. Autophagy 2011;7(8): 910-911.

NeuroMolecular Medicine 2003;4(1): 73-94.

static Regulation. Science 2011;334(6059): 1081-1086.

and beyond. Nat Rev Mol Cell Biol 2012;13(2): 89-102.

naling & Behavior 2011;6(8): 1212-1215.

S102-S109.

R626.

7947-7957.

quences. Journal of Neuroscience Research 1997;50(5): 844-852.

Phenotype of SBMA Mice. PLoS Genet 2011;7(10): e1002321.

Yeast to Mammals. Journal of Biochemistry 2009;146(6): 743-750.

nating glia. Current Opinion in Neurobiology 2009;19(5): 505-510.

### **Author details**

Daniel Radecki1 and Alexander Gow1,2,3\*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA

2 Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

3 Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA

### **References**

[7] Gow A, Lazzarini R. A cellular mechanism governing the severity of Pelizaeus −Merzbacher disease. Nature Genetics 1996;13: 422-428.

**Acknowledgements**

548 Neurodegenerative Diseases

**Author details**

Daniel Radecki1

Detroit, MI, USA

**References**

Medicine, Detroit, MI, USA

Journal 2012;2012: 12.

2001;52(6): 700-708.

PLoS ONE 2012;7(4): e35807.

This work was supported by grants to A.G. from the National Institutes of Health, NINDS,

1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine,

2 Carman and Ann Adams Department of Pediatrics, Wayne State University School of

3 Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA

[1] Coppede F. Genetics and Epigenetics of Parkinson's Disease. The Scientific World

[2] Chen W-T, Hong C-J, Lin Y-T, Chang W-H, Huang H-T, Liao J-Y, Chang Y-J, Hsieh Y-F, Cheng C-Y, Liu H-C, Chen Y-R, Cheng IH. Amyloid-Beta (Aβ) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-Zinc/Copper Assemblies.

[3] Inayathullah M, Teplow DB. Structural dynamics of the ΔE22 (Osaka) familial Alz‐

[4] Gow A, Southwood CM, Lazzarini RA. Disrupted Proteolipid Protein Trafficking Re‐ sults in Oligodendrocyte Apoptosis in an Animal Model of Pelizaeus-Merzbacher

[5] Southwood C, Gow A. Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene. Microscopy Research and Technique

[6] Southwood CM, Garbern J, Jiang W, Gow A. The unfolded protein response modu‐ lates disease severity in Pelizaeus-Merzbacher disease. Neuron 2002;36(4): 585-96.

heimer's disease-linked amyloid β-protein. Amyloid 2011;18(3): 98-107.

Disease. The Journal of Cell Biology 1998;140(4): 925-934.

NS067157 and the National Multiple Sclerosis Society, RG4078 and RG4639.

and Alexander Gow1,2,3\*

\*Address all correspondence to<EMAIL_ADDRESS>

[22] Teske BF, Wek SA, Bunpo P, Cundiff JK, McClintick JN, Anthony TG, Wek RC. The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular Biology of the Cell 2011;22(22): 4390-4405.

[34] Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

551

[35] D'Antonio M, Feltri ML, Wrabetz L. Myelin under stress. Journal of Neuroscience Re‐

[36] Perlman SJ, Mar S, Leukodystrophies Neurodegenerative Diseases, editor, Editor Ed‐

[37] Mar S, Noetzel M. Axonal Damage in Leukodystrophies. Pediatric Neurology

[38] Sakai N. Pathogenesis of leukodystrophy for Krabbe disease: Molecular mechanism

[39] Sawaishi Y. Review of Alexander disease: Beyond the classical concept of leukodys‐

[40] van der Voorn J, van Kollenberg B, Bertrand G, Van Haren K, Scheper G, Powers J, van der Knaap M. The unfolded protein response in vanishing white matter disease.

[41] Castaneda J, Lim M, Cooper J, Pearce D. Immune system irregularities in lysosomal

[42] Powers J, Liu Y, Moser A, Moser H. The inflammatory myelinopathy of adreno-leu‐ kodystrophy: cells, effector molecules, and pathogenic implications. Journal of Neu‐

[43] Garbern J. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cellular

[44] Garbern J, Cambi F, Shy M, Kamholz J. THe molecular pathogenesis of pelizaeus-

[45] Boison D, Stoffel W. Disruption of the compacted myelin sheath of axons of the cen‐ tral nervous system in proteolipid protein-deficient mice. Proceedings of the Nation‐

[46] Griffiths I, Klugmann M, Thomson T, Anderson C, Vouyiouklis D, Nave K-A. Cur‐ rent concepts of PLP and its role in the nervous system. Microscopy Research and

[47] Stecca B, Southwood CM, Gragerov A, Kelley KA, Friedrich VL, Gow A. The Evolu‐ tion of Lipophilin Genes from Invertebrates to Tetrapods: DM-20 Cannot Replace Proteolipid Protein in CNS Myelin. The Journal of Neuroscience 2000;20(11):

Journal of Neuropathology and Experimental Neurology 2005;69(5): 770-775.

and clinical treatment. Brain and Development 2009;31(7): 485-487.

storage disorders. Acta Neuropathologica 2008;115(2): 159-174.

ropathology and Experimental Neurology 1992;51(6): 630-643.

merzbacher disease. Archives of Neurology 1999;56(10): 1210-1214.

and Molecular Life Sciences 2007;64(1): 50-65.

al Academy of Sciences 1994;91(24): 11709-11713.

Technique 1998;41(5): 344-358.

4002-4010.

processes. Trends in Cell Biology 1993;3(6): 191-197.

trophy. Brain and Development 2009;31(7): 493-498.

search 2009;87(15): 3241-3249.

2010;42(4): 239-242.

itors. 2012, Springer US. p. 154-171.

[34] Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular processes. Trends in Cell Biology 1993;3(6): 191-197.

[22] Teske BF, Wek SA, Bunpo P, Cundiff JK, McClintick JN, Anthony TG, Wek RC. The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular Biology of the Cell 2011;22(22):

[23] Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-induci‐ ble gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J

[24] Zou C-G, Cao X-Z, Zhao Y-S, Gao S-Y, Li S-D, Liu X-Y, Zhang Y, Zhang K-Q. The Molecular Mechanism of Endoplasmic Reticulum Stress-Induced Apoptosis in PC-12 Neuronal Cells: The Protective Effect of Insulin-Like Growth Factor I. Endocrinology

[25] Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tu‐

[26] Mak BC, Wang Q, Laschinger C, Lee W, Ron D, Harding HP, Kaufman RJ, Scheuner D, Austin RC, McCulloch CA. Novel Function of PERK as a Mediator of Force-in‐

[27] Saporta MAC, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner D, Crowther M, Southwood C, Wu X, Gow A, Feltri ML, Wrabetz L, Shy ME. MpzR98C arrests Schwann cell development in a mouse model of early-onset

[28] Sharma R, Gow A. Minimal role for caspase 12 in the unfolded protein response in oligodendrocytes in vivo. Journal of Neurochemistry 2007;101(4): 889-897.

[29] Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent Effects of PERK and IRE1 Signal‐

[30] Lin W, Kemper A, Dupree JL, Harding HP, Ron D, Popko B. Interferon-γ inhibits central nervous system remyelination through a process modulated by endoplasmic

[31] Shirakawa K, Maeda S, Gotoh T, Hayashi M, Shinomiya K, Ehata S, Nishimura R, Mori M, Onozaki K, Hayashi H, Uematsu S, Akira S, Ogata E, Miyazono K, Imamura T. CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Regulates Osteo‐

[32] Lin W, Kunkler PE, Harding HP, Ron D, Kraig RP, Popko B. Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to In‐

[33] Bradl M, Lassmann H. Oligodendrocytes: biology and pathology. Acta Neuropatho‐

blast Differentiation. Molecular and Cellular Biology 2006;26(16): 6105-6116.

terferon-γ. The American Journal of Pathology 2008;173(5): 1508-1517.

duced Apoptosis. Journal of Biological Chemistry 2008;283(34): 23462-23472.

Charcot–Marie–Tooth disease type 1B. Brain 2012;135(7): 2032-2047.

4390-4405.

550 Neurodegenerative Diseases

2005;24(6): 1243-1255.

2009;150(1): 277-285.

mor growth. EMBO J 2005;24(19): 3470-3481.

ing on Cell Viability. PLoS ONE 2009;4(1): e4170.

reticulum stress. Brain 2006;129(5): 1306-1318.

logica 2010;119(1): 37-53.

[48] Kagawa T, Ikenaka K, Inoue Y, Kuriyama S, Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K. Glial cell degeneration and hypomyelination caused by over‐ expression of myelin proteolipid protein gene. Neuron 1994;13(2): 427-442.

[60] Kagawa T, Nakao J, Yamada M, Shimizu K, Hayakawa T, Mikoshiba K, Ikenaka K. Fate of Jimpy-Type Oligodendrocytes in Jimpy Heterozygote. Journal of Neurochem‐

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

553

[61] Schneider AM, Griffiths IR, Readhead C, Nave KA. Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin pro‐ teolipid protein. Proceedings of the National Academy of Sciences 1995;92(10):

[62] Gardinier MV, Macklin MB. Myelin proteolipid protein gene expression in jimpy and

[63] Jung M, Sommer I, Schachner M, Nave K-A. Monoclonal Antibody O10 Defines a Conformationally Sensitive Cell-Surface Epitope of Proteolipid Protein (PLP): Evi‐ dence that PLP Misfolding Underlies Dysmyelination in Mutant Mice. The Journal of

[64] Schneider A, Montague P, Griffiths I, Fanarraga M, Kennedy P, Brophy P, Nave K-A. Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid

[65] Baumann NA, Jacque CM, Pollet SA, Harpin ML. Fatty Acid and Lipid Composition of the Brain of a Myelin Deficient Mutant, the "Quaking" Mouse. European Journal

[66] Gencic S, Hudson L. Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice. The Journal of Neuroscience 1990;10(1): 117-124.

[67] Wolf MK, Kardon GB, Adcock LH, Billings-Gagliardi S. Hypomyelinated mutant mice. V. Relationship between jp and jpmsd re-examined on identical genetic back‐

[68] Kassmann CM, Nave KA. Oligodendroglial impact on axonal function and survival -

[69] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sand‐ berg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnos‐ tic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of

[70] Comabella M, Vandenbroeck K. Pharmacogenomics and Multiple Sclerosis: Moving Toward Individualized Medicine. Current Neurology and Neuroscience Reports

[71] Hartung H-P, Lehmann HC, Kieseier BC, Hughes RAC. Novel treatment for immune neuropathies on the horizon. Journal of the Peripheral Nervous System 2011;16(2):

a hypothesis. Current Opinion in Neurology 2008;21(3): 235-241.

jimpy(msd) mice. Journal of Neurochemistry 1988;51(2): 360-369.

istry 1994;62(5): 1887-1893.

Neuroscience 1996;16(24): 7920-7929.

of Biochemistry 1968;4(3): 340-344.

grounds. Brain Res 1983;271(1): 121-129.

Neurology 2011;69(2): 292-302.

2011;11(5): 484-491.

75-83.

protein gene. Nature 1992;358(6389): 758-761.

4447-4451.

[60] Kagawa T, Nakao J, Yamada M, Shimizu K, Hayakawa T, Mikoshiba K, Ikenaka K. Fate of Jimpy-Type Oligodendrocytes in Jimpy Heterozygote. Journal of Neurochem‐ istry 1994;62(5): 1887-1893.

[48] Kagawa T, Ikenaka K, Inoue Y, Kuriyama S, Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K. Glial cell degeneration and hypomyelination caused by over‐

[49] Saher G, Rudolphi F, Corthals K, Ruhwedel T, Schmidt K-F, Lowel S, Dibaj P, Barr‐ ette B, Mobius W, Nave K-A. Therapy of Pelizaeus-Merzbacher disease in mice by

[50] Tatar CL, Appikatla S, Bessert D, Paintlia AS, Singh I, Skoff RP. Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout

[51] Gow A, Friedrich VLJ, R.A. L. Many Naturally Ocurring Mutations of Myelin Proteo‐ lipid Protein Impair Its Intracellular Transport. Journal of Neuroscience Research

[52] Duncan ID, Hammang JP, Trapp BD. Abnormal compact myelin in the myelin-defi‐ cient rat: absence of proteolipid protein correlates with a defect in the intraperiod

[53] Vela JM, González B, Castellano B. Understanding glial abnormalities associated with myelin deficiency in the jimpy mutant mouse. Brain Research Reviews

[54] Griffiths I, Scott I, McCulloch M, Barri J, McPhilemy K, Cattanach BM. Rumpshaker mouse: a new X-linked mutation affecting myelination: evidence for a defect in PLP

[55] Nave K, Bloom F, Milner R. A single nucleotide difference in the gene for myelin pro‐ teolipid protein defines the jimpy mutation in mouse. Journal of Neurochemistry

[56] Nadon NL, Duncan ID, Hudson LD. A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development. Development

[57] Hudson LD, Berndt JA, Puckett C, Kozak CA, Lazzarini RA. Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proceedings

[58] Boison D, Stoffel W. Myelin-deficient rat: a point mutation in exon III (A----C, Thr75----Pro) of the myelin proteolipid protein causes dysmyelination and oligoden‐ drocyte death. The European Molecular Biology Organization 1989;8(11): 3295-3302.

[59] Domanska-Janik K, J. S, A. T. Immunohistochemical study of myelin-specific pro‐

expression. Journal of Neurocytology 1990;19(2): 273-283.

of the National Academy of Sciences 1987;84(5): 1454-1458.

teins in pt rabbits. Folia Neuropathology 1997;35(1): 1-7.

line. Proceedings of the National Academy of Sciences 1987;84(17): 6287-6291.

expression of myelin proteolipid protein gene. Neuron 1994;13(2): 427-442.

feeding a cholesterol-enriched diet. Nature Medicine 2012;18(7): 1130-1135.

the brain. ASN Neuro 2010;2(4).

1994;37(5): 574-583.

552 Neurodegenerative Diseases

1998;26(1): 29-42.

1987;49(6): 1873-1877.

1990;110(2): 529-537.

[72] Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. New England Journal of Medicine 2010;362(5): 387-401.

[84] Whetten-Goldstein K, Sloan FA, Goldstein LB, Kulas ED. A comprehensive assess‐ ment of the cost of multiple sclerosis in the United States. Multiple Sclerosis

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

555

[85] Zhang J, Kramer EG, Asp L, Dutta DJ, Navrazhina K, Pham T, Mariani JN, Argaw AT, Melendez-Vasquez CV, John GR. Promoting myelin repair and return of func‐

[86] Bluestein KT, Pitt D, Knopp MV, Schmalbrock P. T1 and proton density at 7 T in pa‐ tients with multiple sclerosis: an initial study. Magnetic Resonance Imaging

[87] Poloni G, Minagar A, Haacke EM, Zivadinov R. Recent developments in imaging of

[88] Mainero C, Benner T, Radding A, van der Kouwe A, Jensen R, Rosen B, Kinkel R. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI.

[89] Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FMV. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature

[90] Chen F, Shaw MK, Li J, Lisak RP, Tse HY. Adoptive transfer of myelin basic proteininduced experimental autoimmune encephalomyelitis between SJL and B10.S mice: Correlation of priming milieus with susceptibility and resistance phenotypes. Journal

[91] Morgan L, Shah B, Rivers LE, Barden L, Groom AJ, Chung R, Higazi D, Desmond H, Smith T, Staddon JM. Inflammation and dephosphorylation of the tight junction pro‐ tein occludin in an experimental model of multiple sclerosis. Neuroscience

[92] Shaw MK, Kim C, Ho K-L, Lisak RP, Tse HY. A combination of adoptive transfer and antigenic challenge induces consistent murine experimental autoimmune encephalo‐ myelitis in C57BL/6 mice and other reputed resistant strains. Journal of Neuroimmu‐

[93] Tischner D, Weishaupt A, Brandt Jvd, Müller N, Beyersdorf N, Ip CW, Toyka KV, Hünig T, Gold R, Kerkau T, Reichardt HM. Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis. Brain

[94] Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of mul‐ tiple sclerosis via animal models: 70 years of merits and culprits in experimental au‐

toimmune encephalomyelitis research. Brain 2006;129(8): 1953-1971.

tion in multiple sclerosis. FEBS Letters 2011;585(23): 3813-3820.

multiple sclerosis. Neurologist 2011;17(4): 185-204.

1998;4(5): 419-425.

2012;30(1): 19-25.

Neurology 2009;73: 941-948.

2007;147(3): 664-73.

nology 1992;39(1–2): 139-149.

2006;129(10): 2635-2647.

Neuroscience 2011;14(9): 1142-1149.

of Neuroimmunology 2006;173(1–2): 146-154.

[84] Whetten-Goldstein K, Sloan FA, Goldstein LB, Kulas ED. A comprehensive assess‐ ment of the cost of multiple sclerosis in the United States. Multiple Sclerosis 1998;4(5): 419-425.

[72] Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. New England Journal of Medicine

[73] Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phil‐ lips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple

[74] Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M. Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis. New England Journal of

[75] Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. The Lancet;

[76] Fairless R, Williams SK, Hoffmann DB, Stojic A, Hochmeister S, Schmitz F, Storch MK, Diem R. Preclinical Retinal Neurodegeneration in a Model of Multiple Sclerosis.

[77] Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple

[78] Petratos S, Azari M, Ozturk E, Roula O, Papadopoulos R, Bernard C. Novel Thera‐ peutic Targets for Axonal Degeneration in Multiple Sclerosis. Journal of Neuropa‐

[79] Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS. Experimental Autoimmune Ence‐ phalomyelitis (EAE) in CCR2−/− Mice: Susceptibility in Multiple Strains. The Ameri‐

[80] Bradl M, Linington C. Animal models of demyelination. Brain Pathology 1996;6(3):

[81] Becher B, Segal B. TH17 cytokines in autoimmune neuro-inflammation. Current

[82] Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected Neurites, Apoptotic Neurons, and Reduced Inflammation in Cortical Multiple Sclerosis Lesions. Annals

[83] Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, Galea I Natalizu‐ mab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Re‐

views, 2011. CD007621 DOI: 10.1002/14651858.CD007621.pub2.

Sclerosis. New England Journal of Medicine 2006;354(9): 899-910.

The Journal of Neuroscience 2012;32(16): 5585-5597.

thology and Experimental Neurology 2010;69(4): 323-334.

sclerosis. FEBS Letters 2011;585(23): 3715-3723.

can Journal of Pathology 2003;162(1): 139-150.

Opinion in Immunology 2011;23(6): 707-712.

of Neurology 2001;50(3): 389-400.

2010;362(5): 387-401.

554 Neurodegenerative Diseases

378(9805): 1779-1787.

303-311.

Medicine 2012;366(11): 1000-1009.

[95] Gow A, Chapter nine - Using Temporal Genetic Switches to Synchronize the Unfold‐ ed Protein Response in Cell Populations In Vivo, in Methods in Enzymology. 2011, Academic Press. p. 143-161.

[107] Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β-cell

Oligodendrocyte Metabolic Stress in Neurodegeneration

http://dx.doi.org/10.5772/54461

557

[108] Gensicke H, Leppert D, Yaldizli Ö, Lindberg RLP, Mehling M, Kappos L, Kuhle J. Monoclonal Antibodies and Recombinant Immunoglobulins for the Treatment of

[109] He D, Zhou H, Han W, Zhang S Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews, 2011. DOI:

death. Trends in Endocrinology and Metabolism 2011;22(7): 266-274.

Multiple Sclerosis. CNS Drugs 2012;26(1): 11-37.

10.1002/14651858.CD009130.pub2.

[107] Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β-cell death. Trends in Endocrinology and Metabolism 2011;22(7): 266-274.

[95] Gow A, Chapter nine - Using Temporal Genetic Switches to Synchronize the Unfold‐ ed Protein Response in Cell Populations In Vivo, in Methods in Enzymology. 2011,

[96] Abraira V, Alvarez-Cermeño JC, Arroyo R, Cámara C, Casanova B, Cubillo S, de An‐ drés C, Espejo C, Fernández O, Ferrer J, Figueredo MA, García-Merino A, García-Sánchez MI, García-Trujillo JA, Gómez M, González-Oria C, Gosis A, Izquierdo G, Jímenez J, López-Trascasa M, Montalbán X, Moreno MJ, Muñoz D, Nuñez V, Muriel A, Navarro J, Olascoaga J, Oreja-Guevara C, Prada A, Ramil E, Ramo-Tello C, Rodrí‐ guez C, Rodríguez E, Rodríguez-Frías F, Rodríguez-Antigüedad A, Rodríguez-Moli‐ na JJ, Ruiz E, Saiz A, Sarasola E, Simó M, Yagüe J, Villar LM. Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice. Journal of Immunolog‐

[97] Denic A, Macura S, Mishra P, Gamez J, Rodriguez M, Pirko I. MRI in Rodent Models

[98] Patel NH, Vyas NS, Puri BK, Nijran KS, Al-Nahhas A. Positron Emission Tomogra‐ phy in Schizophrenia: A New Perspective. Journal of Nuclear Medicine 2010;51(4):

[99] Rigotti DJ, Inglese M, Gonen O. Whole-Brain N-Acetylaspartate as a Surrogate Mark‐ er of Neuronal Damage in Diffuse Neurologic Disorders. American Journal of Neu‐

[100] Tartaglia MC, Arnold DL. The role of MRS and fMRI in multiple sclerosis. Advanced

[101] Lewellen T, Williams D, Olson D. Image quality with nuclear magnetic resonance imaging systems. American Journal of Roentgenology 1981;137(5): 1092-1093. [102] Geurts JJG, Barkhof F. Grey matter pathology in multiple sclerosis. The Lancet Neu‐

[103] Tang KS, Shapiro EM. Enhanced magnetic cell labeling efficiency using –NH2 coated

[104] De Stefano N, Filippi M, Miller D, Pouwels PJ, Rovira A, Gass A, Enzinger C, Mat‐ thews PM, Arnold DL. Guidelines for using proton MR spectroscopy in multicenter

[105] Kumar A, Asano E, Chugani HT. α-[11C]-methyl-L-tryptophan PET for tracer locali‐ zation of epileptogenic brain regions: clinical studies. Biomarkers in Medicine

[106] Kadir A, Nordberg A. Target-Specific PET Probes for Neurodegenerative Disorders Related to Dementia. Journal of Nuclear Medicine 2010;51(9): 1418-1430.

MPIOs. Magnetic Resonance in Medicine 2011;65(6): 1564-1569.

clinical MS studies. Neurology 2007;69(20): 1942-52.

Academic Press. p. 143-161.

ical Methods 2011;371(1–2): 170-173.

roradiology 2007;28(10): 1843-1849.

Neurology 2006;98: 185-202.

rology 2008;7(9): 841-851.

2011;5(5): 577-584.

511-520.

556 Neurodegenerative Diseases

of Brain Disorders. Neurotherapeutics 2011;8(1): 3-18.

**Section 4**

**Miscellaneous**

**Section 4**

### **Miscellaneous**

**Chapter 23**

**Spinal Muscular Atrophy: Classification,**

**and Development of Therapeutics**

Faraz Tariq Farooq, Martin Holcik and

Additional information is available at the end of the chapter

Alex MacKenzie

**1. Introduction**

of SMA.

**2. Epidemiology**

of infant death globally [1-5].

http://dx.doi.org/10.5772/53800

**Diagnosis, Background, Molecular Mechanism**

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease and one of the most common genetic causes of infant death. The loss or mutation of the SMN1 gene results in reduced SMN protein level leading to motor neuron death and progressive muscle atrophy. Although recent progress has been made in our understanding of the molecular mechanisms underlying the pathogenesis of the disease, there is currently no cure for SMA. In this review, we summarize the clinical manifestations, molecular pathogenesis, diagnostic strategy and development of therapeutic regimes for the better understanding and treatment

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder character‐ ized by the loss of motor neurons from the anterior horn of the spinal cord which leads to muscle weakness, hypotonia and ultimately muscle atrophy [1]. With a pan ethnic incidence of 1:11,000 live births and a carrier frequency of 1:50, SMA is one of the leading genetic causes

> © 2013 Farooq et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.