traditionally , the major mechanism underlying parkinson 's disease was thought to be reduced dopaminergic synaptic transmission in the nigrostriatal system .
however , neurons may also communicate by extrasynaptic transmission , which was recently found to affect dopamine neurotransmitter delivery through diffusion in the extracellular matrix .
fibronectin , a ubiquitous extracellular matrix component , participates in the formation and regulation of anisotropic diffusion ( i.e. , diffusion facilitated in a certain direction ) of the extracellular matrix , and dynamically regulates neuronal functional activities , such as neuroactive substance diffusion and receptor activation , anti - neuroinflammation , and cell adhesion .
studies over the past two decades have demonstrated that there exist two major modes of neuron - glial communication in the central nervous system : synaptic transmission ( or wiring transmission ) and extrasynaptic transmission . in synaptic transmission ,
synaptically evoked astrocytes produce elevated ca signals , which can trigger the release of gliotransmitters and play neuromodulatory and information - integration roles in neuronal activity , synaptic transmission and plasticity .
extrasynaptic transmission involves secretion of a wide variety of bioactive substances by neurons and neuroglia that are released or leaked into the extracellular space .
these substances mediate bidirectional communication between neurons and neuroglia through molecular diffusion , resulting in a sustained neuromodulatory action on neuronal activity .
,  volume transmission  and  intercellular communication  , all of which reflect the specific function of extracellular space .
there are four types of extrasynaptic transmission in the central nervous system ( figure 1 ) : including the intercellular short distances , the cerebrospinal fluid , the long distances around nerve fibers , and long distances around blood vessels .
the latter two types of extrasynaptic transmission display the properties of faster and longer signal transmission that occur among brain nuclei , cerebral areas and even cerebral hemispheres , and involve the movement of various bioactive substances , such as ions , neuropeptides , neurohormones and metabolites , as well as pathological hematologic exudates such as cell adhesion molecules , growth factors and inflammatory molecules .
thus , extrasynaptic transmission plays important modulatory roles in neuronal functional activities . in the central nervous system
, fibronectin is produced and secreted by neuroglial cells and endothelial cells and is assembled into the extracellular matrix .
thus , fibronectin is important for extrasynaptic transmission , and to some degree exerts neuroprotective effects , such as anti - neuroinflammation .
however , the neuroprotective mechanism of fibronectin remains to be thoroughly analyzed to reveal its important clinical value and to enhance understanding of extrasynaptic transmission and the functional role of the neuron- glia network . in turn , it is hoped that this knowledge will unveil the molecular pathogenesis and new therapeutic approaches in neurodegenerative disorders such as parkinson 's disease .
here , we summarize the molecular structures and roles of fibronectin and integrin receptors in extrasynaptic transmission , the neuroprotective roles of fibronectin and its potential significance in parkinson 's disease . schematic diagram of the principal types of cerebral extrasynaptic transmission ( modified and adapted from references ) .
the four types of extrasynaptic transmission in the central nervous system involve :  short distances for simple diffusion , such as autocrine and paracrine transmission ,  cerebrospinal fluid ( csf ) for endocrine diffusion ,  long distances around nerve bundles for preferential diffusion , and  long distances around blood vessels for preferential diffusion .
the left section shows the functional tracks of extrasynaptic transmission or volume transmission , and the right section shows the functional tracks of synaptic transmission ( neural wiring transmission ) without neuroactive substance leakage into the extracellular space .
fibronectin is a heterodimeric glycoprotein encoded by a single gene and is disulfide - bonded at its carboxyl terminal .
each monomer contains three types of repeats ( type i , ii or iii ) and constitutes multiple domains .
the middle domain contains an arg - leu - asp ( rgd)-binding motif that can bind to integrin and non - integrin receptors .
the carboxyl terminal domain containing a heparin binding site and a variable sequence has a higher expression level in the embryonic period that becomes lower in the elderly , and displays a neuroprotective effect .
fibronectin has a wide variety of cell sources , such as astrocytes , epithelial cells , fibroblasts , and mesenchymal cells , and participates in cell adhesion , proliferation and differentiation , epithelial tissue repair , immune regulation , neural regeneration , and other physiological activities .
integrins , the receptors for fibronectin , are a family of transmembrane glycoprotein receptors and their molecular structure comprises one  and one  subunit bound by non - covalent bonds
. they can recognize and bind to fibronectin and other extracellular matrix proteins or other receptors , and exert dual functions of cell adhesion and signal transduction . at present
, it is well - established that there are nineteen  and eight  subunits that can combine to form at least 25 different integrin receptors in mammals .
the majority of  subunits only bind to one  subunit and sometimes to multiple  subunits , such as 41 , 47 , 61 , 64 , v1 , v3 , v5 , v6 and v8 .
both  and  subunits have a large extracellular region ( important for binding to the rgd sequence in various integrin ligands such as matrix molecules ) , a transmembrane region and a small intracellular region ( no catalytic effect ) .
integrins are functionally divided into three main subfamilies : 1 integrins ( i.e. , very late antigen integrins ) , 2 integrins ( i.e. , leukocyte integrins ) , and v integrins , with 3 integrins ( i.e. , cell adhesion integrins ) also given more attention recently .
that is , the binding of an integrin to its ligand can activate intracellular signaling events , which in turn affect the affinity of ligand and integrin . in most cases , integrins can combine with neighboring receptors ( i.e. , counter receptors ) to form integrin - receptor complexes , or receptor mosaics , on the cell surface that transactivate intracellular signaling and modulate biological effects .
for example , in the cerebrovascular endothelial cells , fibronectin mediates the mitogen - activated protein kinase signaling pathway via 51 and v3 receptors and promotes cell survival and proliferation .
moreover , fibronectin plays a neurotrophic and anti - inflammatory role in the brain and promotes the growth and survival of neurons .
it has been confirmed that the fibronectin type iii ( fibronectin 3 ) modules of the neural cell adhesion molecule are involved in the direct interaction between neural cell adhesion molecule and fibroblast growth factor receptor in dopaminergic , hippocampal and cortical neurons , and then activate the mitogen - activated protein kinase and phosphatidylinositol 3-kinase / protein kinase b ( pi3k / akt ) signal transduction pathways and induce neuronal differentiation and proliferation in vitro .
the administration of synthetic fibronectin peptide v can increase the survival of dopaminergic neurons in neural grafts in vivo and ameliorate motor dysfunction in parkinson 's disease animals , suggesting the anti - apoptotic effect of fibronectin .
fibronectin can also inhibit the development of mechanical allodynia by injection into the spinal dorsal column after spinal injury .
in microglia , fibronectin can activate the pi3k - akt and mitogen - activated protein kinase / extracellular signal - regulated kinase signaling pathway , enhance the expression levels of neurotrophic factors , and attenuate the release of the pro - inflammatory factor interleukin 1 , all of which contribute to neural repair and neuronal survival .
traumatic brain injury induced significantly increased lesion volume and apoptotic cell death in fibronectin knockout mice , but intravenous injection of fibronectin before the injury reversed the neural deficits , indicating that fibronectin is neuroprotective against traumatic brain injury and a novel target for therapeutic interventions .
fibronectin can also promote survival and migration of transplanted primary neural stem cells in a mouse model of traumatic brain injury , and act as a possible therapeutic tool for traumatic brain injury .
taken together , findings from the studies on the neuroprotective role of fibronectin are expected to lead to the development of new therapeutic approaches for parkinson 's disease and other neurodegenerative diseases , and indicate that fibronectin could become an important pharmacological tool for the study of specific functional aspects of extrasynaptic transmission , including neuroprotection and neuromodulation .
the three major subfamilies ( 1 , 2 and v ) of integrins are all able to recognize and bind to extracellular matrix proteins and counter receptors and trigger a great deal of intracellular structural and signaling changes .
these changes include the assembly of multi - molecular complexes onto cytoplasmic integrin tails to engage and organize the cytoskeleton , as well as the activation of signaling pathways that modify function and gene expression .
cross - talk between integrin - mediated signaling and growth factor - mediated signaling can occur at various levels .
furthermore , integrin - fibronectin ligand interactions play roles in cell adhesion , and in combination with growth factor receptors , regulate functional activities of growth factors via receptor transactivation and intracellular signaling events . in the central nervous system , 1 and v are extensively expressed in several cell types such as neurons , glia and epithelial cells , while 2 is only expressed in microglia .
51 is the only integrin receptor containing the 5 subunit and binds to only one fibronectin ligand , which , along with 31 and 41 , promotes growth and regulates function in neural cells and cerebrovascular endothelial cells .
it has been demonstrated that 1 and v integrins can transactivate a variety of growth factor receptors and mimic the somatotrophic or neuroprotective effect of related growth factors , such as fibroblast growth factor , insulin - like growth factor ( igf)-1 and glial cell line - derived neurotrophic factor . in the dopaminergic neurons of the substantia nigra that have a high level of constitutive igf-1 receptor ( igf-1r ) expression ,
1 integrins ( e.g. , 3 , 4 , 51 ) can activate the igf-1r/ phosphatidylinositol 3-kinase / protein kinase b signaling pathway by the igf-1-independent transactivation of igf-1r , and enhance igf - mediated neurotrophic effects in degenerating dopaminergic neurons .
for example , fibronectin is abundant in pancreatic tumors and engages igf - ir to inhibit cell death by stimulating formation of a complex between 3 integrin and protein - tyrosine phosphatase shp-2 .
formation of this complex prevents shp-2 from dephosphorylating igf - ir and results in sustained phosphorylation of igf - ir and downstream activation of akt kinase , and the inhibition of apoptosis through up - regulation of the anti - apoptotic factor bcl .
1 integrin expression is required for igf - ir - mediated prostate cancer cell proliferation and anchorage - independent growth , and can bring about the extended activation of igf-1r and mimic and amplify the biological effects of igf-1 .
therefore , fibronectin - induced neuroprotection could be fully mediated by igf - ir without involvement of igf-1 , suggesting that fibronectin and igf - ir could be important targets for the development of pharmaceuticals that mediate pro - survival signals .
fibronectin is a non - collagen component among extracellular matrix proteins that are synthesized by many cell types , such as astrocytes , endothelial cells , fibroblasts and myoblasts .
extracellular matrix proteins are then assembled into three - dimensional fibrillar networks surrounding neural cells to form a pericellular microenvironment and to support biomolecular flow .
however , this microenvironment is not homogeneous allowing for the directional facilitation of information flow down different dynamic pathways , i.e. , intercellular channels , to regulate neuron - glial extrasynaptic transmission . during brain development or injury , fibronectin and other matrix proteins may support and promote differentiation and migration of neuronal progenitor cells , or directional outgrowth of neurites . in the adult brain , the fibrillar fibronectin guides and
controls the flow of extracellular fluid and the diffusion of various substances , which are driven by energy gradients , such as concentration , temperature and pressure gradients , and have slower diffusion properties , less safety , less spatial constraint and wider diffusion ranges .
the diffusion capability of extrasynaptic transmission is determined by three parameters : 1 ) extracellular space volume fraction  (  = extracellular space volume / total tissue volume ) , which can be reduced due to cerebral atrophy in the elderly , especially in neurodegenerative diseases , 2 ) tortuosity  , reflecting the condition of diffusion barriers such as altered fibrillar fibronectin architecture and other extracellular matrix macromolecules , fine neural processes , charged molecules and degrading enzymes , 3 ) nonspecific cellular uptake ( k ) , indicating the degree of cell swelling .
these diffusion parameters differ in various brain regions , showing heterogeneous diffusion in the central nervous system , and are easily affected by physiological and pathological factors such as molecular rearrangement , glial remodeling , cell swelling and elderly extracellular space shrinkage .
therefore , the expression level of fibronectin can directly influence the diffusion and permeability of various neuroactive substances , to some degree by directional facilitation through intercellular channels due to local changes in homeostasis .
these preferential channels exert an important regulatory role on neurotransmitter diffusion , and intercellular short distance and peri - neurofiber long distance extrasynaptic transmission .
thus , they might adversely underlie disease pathology and be used as a potential target for the treatment of neurodegenerative diseases such as parkinson 's disease . in geriatric patients , there are significant alterations in volume , tortuosity and anisotropy of brain extracellular space .
these changes may seriously affect intercellular channel permeability and communication through the neuron - glia network , and bring about synapse - transmitter leakage and transmitter - receptor mismatches that give rise to abnormal accumulation and diffusion of neuroactive substances .
this mechanism might contribute to the pathogenesis of parkinson 's disease or other neurodegenerative diseases , and provide a pharmacological target to ameliorate deficiencies in neurotransmission , cell migration and drug delivery and treatment .
along with other components of the extracellular matrix , such as glycosaminoglycans and proteoglycans , fibronectin accumulates in the extracellular matrix to form poriferous perineuronal nets to regulate matrix organization . for example , fibronectin may specifically bind to growth factor receptors or be involved in clearance of degraded products and direct cell behaviors , such as receptor activation that transduces signals into cells , in addition to its supportive and adhesive roles .
these effects of fibronectin could bring about the altered structural and functional properties of extracellular matrix ( e.g. , neurotransmitter storage , metabolite clearance , and diffusion parameters ) , and underlie the molecular mechanism of neurodegenerative disorders such as parkinson 's disease .
the expression level of fibronectin determines the nature and condition of extracellular matrix , and is readily affected by multiple physiological and pathological factors ( e.g. , ageing and neuroinflammatory response ) , as well as genetic and epigenetic factors ( e.g. , transcription factors and post - translational modifications ) .
meanwhile , fibronectin , like other extracellular matrix macromolecules , contributes to diffusion barriers in the extracellular space and influences neuroglial activation , diffusion of various factors or neurotransmitters , information transmission and neurotrophic microenvironment , in spite of neuronal and glial processes also disturbing the local extracellular matrix architecture of the central nervous system .
briefly , binding of fibronectin to integrins ( 1 , 2 , and v ) triggers intracellular structural alterations and signaling cascades , including integrin - mediated signaling which can crosstalk with growth factor - mediated signaling at various levels and mimic the functions of growth factors via receptor transactivation and intracellular signaling events .
therefore , fibronectin could be applied to study neuroprotection in neurodegenerative diseases such as parkinson 's disease . in the parkinson 's disease brain , the transmission of dopamine in the nigrostriatal pathway is greatly abated or blocked for two reasons : 1 ) deficit of striatal dopamine in the parkinson 's disease brain because of decreased dopamine synthesis in degenerating nigral neurons , and 2 ) altered matrix content and increased diffusion barriers to extrasynaptic transmission along the nigrostriatal pathway .
the latter is the main pathological change in the parkinson 's disease brain because the nigrostriatal dopamine pathway mainly operates via volume transmission ; that is , nigral dopamine reaches target cells mostly by diffusion along the dopamine concentration gradient of the extracellular space .
although the downregulated expression of fibronectin in the elderly brain can compensative and reduce the diffusion barrier and partly ameliorate deficits in dopamine diffusion , the increased volume fraction is still not reversed .
therefore , fibronectin could be administered as a neuroprotective drug to augment the fibronectin levels in plasma and brain , which would not only enhance survival of dopaminergic neurons but would also maintain a better extracellular matrix status for unrestricted diffusion and traffic of dopamine along the nigrostriatal pathway .
in particular , under circumstances in which wiring transmission is blocked , the use of extrinsic fibronectin has an important compensatory effect on the striatal dopamine deficit and protects against the development of parkinson 's disease .
moreover , it is reasonable to predict that the molecular status of plasma fibronectin could be used as an additional diagnostic biomarker for risk assessment of parkinson 's disease , and that the increase of fibronectin in the cerebrospinal fluid could be an important parameter used to diagnose certain neurodegenerative diseases such as amyotrophic lateral sclerosis and multiple sclerosis .
the proneuronal and metabolic effects of fibronectin will be helpful in formulating new therapeutic and diagnostic strategies .
fibronectin can bind to and activate both integrin receptors and igf-1r , thus triggering igf-1r / phosphatidylinositol 3-kinase / protein kinase b signaling and enhancing survival of dopamine neurons .
we refer to this cascade ( summarized in figure 2 ) as the  fibronectin - integrin - growth factor receptor - signal transduction - gene and protein expression cascade  , through which altered extrasynaptic transmission may modulate the functional outputs of cells to compensate for deficits in synaptic transmission .
therefore , fibronectin could likely be used as an endogenous repair protein of extracellular matrix , and its clinical application ameliorate the poor brain extracellular environment and achieve some therapeutic effects in neurodegenerative diseases .
the study of the functional manipulation of fibronectin in neuron - glial extrasynaptic transmission should be expanded to broaden our understanding of the complex fibronectin- and integrin - mediated signaling networks , and to determine a new and effective approach to diagnosis and treatment of certain neurodegenerative diseases . a proposed schematic map of the neuroprotective mechanism of fibronectin .
fibronectin may mediate a receptor - receptor interaction between integrins and igf-1r in the cell surface membrane .
molecular cross - talk likely occurs between the intracellular signaling cascades resulting from this interaction , to finally produce the neuroprotective effects .
trk : tyrosine receptor kinase ; igf-1r : insulin - like growth factor-1 receptor ; mek : mitogen - activated protein kinase kinase ; erk : extracellular signal - regulated kinase ; pi-3k / akt : phosphatidylinositol 3-kinases / protein kinase b.
 most hypotheses concerning the mechanisms underlying parkinson 's disease are based on altered synaptic transmission of the nigrostriatal system . 
 however , extrasynaptic transmission was recently found to affect dopamine neurotransmitter delivery by anisotropic diffusion in the extracellular matrix , which is modulated by various extracellular matrix components such as fibronectin . 
 the present study reviewed the neuroprotective effect of fibronectin in extrasynaptic transmission . 
 fibronectin can regulate neuroactive substance diffusion and receptor activation , and exert anti- neuroinflammatory , adhesive and neuroprotective roles . 
 fibronectin can bind to integrin and growth factor receptors to transactivate intracellular signaling events such as the phosphatidylinositol 3-kinase / protein kinase b pathway to regulate or amplify growth factor - like neuroprotective actions . 
 fibronectin is assembled into a fibrillar network around cells to facilitate cell migration , molecule and ion diffusion , and even drug delivery and treatment . 
 in addition , the present study analyzed the neuroprotective mechanism of fibronectin in the pathogenesis of parkinson 's disease , involving integrin and growth factor receptor interactions , and discussed the possible therapeutic and diagnostic significance of fibronectin in parkinson 's disease . 
INTRODUCTION
MOLECULAR STRUCTURE AND FUNCTIONS OF FIBRONECTIN AND ITS INTEGRIN RECEPTORS
NEUROPROTECTIVE ROLE OF FIBRONECTIN AND ITS MOLECULAR MECHANISM
FIBRONECTIN IS A CONSTITUTIVE COMPONENT AND REGULATOR OF EXTRASYNAPTIC TRANSMISSION
ROLES OF FIBRONECTIN IN NEURON-GLIAL EXTRASYNAPTIC TRANSMISSION AND PATHOGENESIS
CONCLUSION