recent studies demonstrate roles for regulatory noncoding rna molecules ( ncrnas ) in normal cns development and function and in the onset and progression of various neurodegenerative diseases .
ncrnas are functional rna molecules expressed specifically in the central nervous system that do not encode proteins .
they are classified as small ncrnas comprising fewer than 400 nucleotides and long ncrnas comprising more than 400 nucleotides .
small ncrnas include ribosomal rnas ( rrnas ) , transfer rnas ( trnas ) , small nucleolar rnas ( snrnas ) , micrornas ( mirnas ) , short small interference rnas ( sirnas ) , and piwi - interacting rnas .
long noncoding rnas ( lncrnas ) include heterogeneous regulatory molecules such as long intergenic noncoding rnas ( linc rnas ) and natural antisense transcripts ( nats ) [ 13 ] .
ncrnas play critical roles in neuronal processes such as transcription of neuronal genes , brain morphogenesis , neuronal cell specification , and formation of memory .
micrornas ( mirnas ) are small rna molecules ( 2123 nucleotides ) involved in the regulation of gene expression that bind posttranscriptionally to the 3-untranslated region of target mrnas and either inhibit translation or degrade the target mrna .
a single - stranded rna , mirna , is derived from a 70100-nucleotide hairpin precursor called pre - mirna that plays a key role in posttranscriptional regulation of target gene expression . due to their small size , mirnas are potentially a valuable tool for therapy of cancer , neurodegenerative , and cardiovascular diseases [ 5 , 6 ] . the mirnas are transcribed by either rna polymerase ii or iii in the nucleus to yield primary transcripts ( pri - mirnas ) of different lengths that are processed by the drosha / dgcr8 enzyme complex into a ~70 base pair precursor mirna .
the precursor mirnas are transported into the cytoplasm where cytoplasmic rnase iii enzymes , dicer and loquacious , process them into ~22-nucleotide mirna duplexes with guide and passenger strands .
the guide strand functions as a mature mirna and is incorporated into an rna - induced silencing complex ( risc ) .
this complex contains an argonaute ( ago ) protein as a primary component that binds to the target mrna and degrades the passenger strand .
mature mirna guides risc to recognize target sequences located in the 3utr of mrnas , which leads to the inhibition of translation or degradation of mrna [ 6 , 7 ] .
neurodegeneration refers to the death of neurons during the normal course of brain development , and many studies demonstrate the involvement of mirnas .
the mirnas are key regulators of cns development involving brain plasticity , neuronal cell maturation , neuronal cell differentiation , and synaptogenesis [ 8 , 9 ] .
dysregulation of mirnas leads to the development of neurodegenerative diseases such as alzheimer 's disease , parkinson 's disease , and huntington 's disease .  
alzheimer 's disease ( ad ) is the most common form of dementia , among elderly adults , and causes memory impairment as well as problems with thinking , decision - making , and behavior .
ad is characterized by dysregulated processing of amyloid precursor protein ( app ) and the accumulation of amyloid beta ( a ) peptide in brain hippocampus .
-secretase , also known as -site app - cleaving enzyme 1 ( bace 1 ) , cleaves app to generate a peptides .
several studies show that increased expression of app , an integral membrane protein , is associated with ad .
.   showed that mir-101 negatively regulates the expression of app and a accumulation in cultured hippocampal neurons , thus suggesting an essential role for mirna in the development and progression of ad .
postmortem studies of human brain hippocampus showed increased levels of bace1 , upregulation of mir-9 , mir-125b , and mir-125b , mir-146a , and downregulation of mir-15a , mir-107 , and mir-29a / b-1 , which suggests a link between mirnas and protease in the progression of the disease [ 3 , 9 ] .
decrease in the expression of mir-107 was observed in patients who exhibit early stages of ad .
affymetrix exon array microarrays demonstrated a sharp increase in bace1 mrna expression and a decrease in mir-107 expression .
in addition , the mir-29a / b-1 cluster is down - regulated in ad patient 's brain while upregulation of bace1 is observed , which suggests a role for the mir-29a / b-1 cluster in negative regulation of bace1 expression that leads to the accumulation of a peptide .
certain patterns of mirna expression in the grey matter of cortex also lead to ad pathogenesis .
mir-211 is downregulated in alzheimer 's disease brain , whereas there is an upregulation of mir-424 .  
a murine model of ad showed that there was no correlation between bace1 mrna and levels of proteins in the hippocampus of appswe / ps1 mice .
.   supports the concept that there is an association between dysfunctional mirna regulation of bace1 expression and ad by further analysis of mir-298 and mir-328 in the hippocampus of appswe / ps1 mice .
in addition , a novel noncoding rna 17a expressed in human brain is upregulated in cerebral tissues of ad patients and leads to increased secretion of a peptides , gpr51 alternative splicing , and ultimately , impaired gaba b function .
a similar study showed that neuroblastoma differentiation marker 29 ( ndm29 ) , a rna polymerase iii - dependent noncoding rna , enhances the synthesis of amyloid precursor protein , eventually resulting in an increase of a secretion that promotes the formation of a peptides as they may occur in alzheimer 's disease .
nf-b signaling regulates mir-146a , which is upregulated in ad brains , and downregulation of cfh protein is observed in ad brains , which suggests that mir-146a targets cfh protein , a brain inflammatory response repressor .
the death of dopamine generating cells in the brain substantia nigra and accumulation of alpha - synuclein leads to the development of parkinson 's disease , which is characterized by motor abnormalities and sensory , mood , and cognitive changes .
a study suggests that -synuclein is regulated posttranscriptionally by mir-7 and mir-153 , which bind directly to the 3-untranslated region of  synuclein and suppress its expression .
in addition , downregulation of  synuclein due to mir-7 and mir-153 protects cells from oxidative stress . in primary neurons ,
increased translation of a luciferase construct that bears  synuclein 3-untranslated region was reportedly caused by inhibition of micro - rnas mir-7 and mir-153 .
elevated levels of fibroblast growth factor 20 ( fgf20 ) genes also lead to overexpression of  synuclein and eventually to the death of dopaminergic neurons .
furthermore , this demonstrates that binding of mir-433 to a single nucleotide polymorphism in the promoter region of fgf20 disrupts the target site for mir-433 , which eventually results in overexpression of  synuclein .
downregulation of mir-7 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(mptp- ) induced neurotoxin pd mouse model suggests that it may protect cells against oxidative stress .
the most vital gene in parkinson 's disease , lrrk2 that functions in the dopamine generating cells negatively regulates let-7 and mir-184 , which causes overexpression of their targets e2f1 and dp eventually , leads to defects in cell division and cell death .
expression of mir-133b is detected in the midbrain dopaminergic neurons but not detected in parkinson 's disease midbrain tissue . a negative feedback loop with the transcription factor pitx3 , found in midbrain dopamine generating neurons , is formed by the downregulation of mir-133b , which is a dopaminergic neuron - specific mirna .
furthermore , a recent study suggests that overexpression of  synuclein by mir-433 leads to increased risk of ad . also ,
activation of two neuroprotective genes pten - induced putative kinase ( pink1 ) and parkinson disease 7 ( park7 ) normally involved in protecting cells from oxidative stress leads to development of parkinson 's disease through pten signaling .  
huntington 's disease is an autosomal dominant neurodegenerative disease characterized by cognitive decline and impaired movement .
it is caused by trinucleotide expansion in the gene that encodes a polyglutamine stretch near the n - terminus of huntingtin .
multiple studies of mirnas in mouse and human brain have shown mir-22 , mir-29c , and mir-128 are down - regulated in mice and mir-9/9 * , mir-29b , and mir-124a are down - regulated in humans [ 25 , 26 ] .
showed that mir-221 and mir-222 are both down - regulated in hd . also , downregulation of mirnas let-7a , let-7c , let-7d , and let 7e was observed in hd - fc ( frontal cortex ) and hd - st ( striatum ) whereas there was upregulation of mir-30b , mir-30c , and mir-30e in hd - fc and hd - st .
the mir-30a , that is , upregulated in hd - fc and hd - st has been shown to target bdnf , which is a rest - modulated neuronal gene .
loss of bdnf leads to loss of medium spiny neurons [ 28 , 29 ] rest / corest regulates many mirnas .
rest repressor complex regulates mir-9 and mir-9 * that target rest / corest expression and are considered to be a part of a double - negative feedback loop .
expression of mir-9/9 * , mir-124a , and mir-132 is regulated by the rest repressor complex including msin3 , rest corepressor 1 ( corest ) , and mecp2 .
rest silencing complex and mir-9/9 * give rise to a negative feedback loop during the development of huntington 's disease due to the effects of mir-9 and mir-9 * on rest and corest .
several mirnas such as mir-9/9 * , mir-129a , mir-132 , mir-29b , mir-29a , mir-330 , mir-17 , mir-196 , mir-222 , mir-485 , and mir-486 are affected in hd due to the disrupted mirna transcriptome [ 27 , 30 ] .
moreover , reports suggest that mir-34b is elevated in plasma of huntington 's disease patients even before the onset of symptoms , which implies that mir-34b may be useful as a potential diagnostic biomarker for hd [ 32 , 33 ] .
clearly , there is evidence for mirnas as potential biomarkers to aid in the diagnosis of neurodegenerative diseases . for instance
, rna interference ( rnai ) knocks down the translation of certain disease - associated molecules due to the presence of short hairpin rnas , synthetic double - stranded rnas , and the precursors of artificial mirnas that are expressed by viral vectors .
these drugs are synthetic rna molecules that mimic a mechanism of action similar to that of endogenous ncrnas  sirnas or mirnas .
thus , rna interference technology has emerged as a potential therapeutic tool for several neurodegenerative diseases . wang et al .  
suggest the following two different potential roles of mir-146 : ( 1 ) as a useful biomarker in the early diagnosis of ad since it can be detected in human blood monocytes , which aids in easy collection , and ( 2 ) as a therapeutic tool .
they also suggest that anti - mir-146a can be used with therapeutic potential to suppress the up - regulatory effects of mir-146 .
another study conducted to examine the pattern of a driven neurogenesis in a transgenic mouse model of ad - tg-19959 showed that the use of lna - modified sirnas led to a marked decrease in the levels of insoluble a peptides and altered the pattern of aggregation of soluble a in the tg-19959 mouse brain by targeting bace1 and bace - as .
identified two diagnostic biomarkers : dysregulation of mirna in ad patients ' brains and changes in mirna specific to ad in cerebrospinal fluid .
several mirnas such as mir-133b , mir-7 , mir-153 , let-7 , mir184 , and mir-433 may be involved in the pathophysiology of pd and offer a novel approach for therapeutic targets .
in addition , the mirna pathway is known to play a crucial role in translational regulation in the pathophysiology of pd and hence is considered one of the most important translation regulation pathways .  
( 2005 ) showed notable signs of improvement in the behavioral abnormalities and neuropathology among hd patients with the use of an adenoassociated virus serotype 1 ( aav1 ) vector that targets the mutant human htt in the brain of mouse giving rise to u6 promoter - driven shrna effector system .
in addition , noncoding small rna - based technology plays a pivotal role in the treatment of huntington 's disease .
antisense oligonucleotides ( aos ) help to prevent mrnas bearing mutations by redirecting pre - mrna splicing .
overall , data suggest that various noncoding rnas could serve as useful diagnostic biomarkers and therapeutic targets for neurodegenerative diseases .
ncrnas , especially mirnas , are known for their roles in normal development and function of the central nervous system .
they are involved in targeted gene expression and act as key regulators in several neuroprotective mechanisms .
it is a well - established fact that dysregulation of mirnas eventually leads to the development of various neurodegenerative diseases .
alterations in the patterns of mirna expression will probably serve as diagnostic biomarkers of brain function , and the initiation and progression of neurological disorders and neurodegenerative diseases .
further research in mirna expression patterns and profiling will result in the discovery of many more novel biomarkers . in - depth study to determine the functions of long noncoding rnas in rna - mediated gene regulation is likely to remain an area of intense research interest .
 noncoding rnas are widely known for their various essential roles in the development of central nervous system . 
 it involves neurogenesis , neural stem cells generation , maintenance and maturation , neurotransmission , neural network plasticity , formation of synapses , and even brain aging and dna damage responses . in this review 
 , we will discuss the biogenesis of microrna , various functions of noncoding rna 's specifically micrornas ( mirnas ) that act as the chief regulators of gene expression , and focus in particular on misregulation of mirnas which leads to several neurodegenerative diseases as well as its therapeutic outcome . 
 recent evidences has shown that mirnas expression levels are changed in patients with neurodegenerative diseases ; hence , mirna can be used as a potential diagnostic biomarker and serve as an effective therapeutic tool in overcoming various neurodegenerative disease processes . 
1. Introduction
2. Biogenesis of MicroRNAs
3. The Role of miRNAs in Neurodegenerative Diseases
4. Applications/Therapeutic Role
5. Future Projections