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the discovery of small noncoding mirnas uncovered an intriguing additional level to the fine - tuning of the transcriptome and proteome .
since their discovery almost 20 years ago [ 1 , 2 ] , research has progressed considerably towards gaining a better understanding of the impact of the complex network of gene regulation by mirnas on health and disease .
this is well documented in the cancer field , for instance , where mirnas are increasingly acknowledged as potential diagnostic and therapeutic agents [ 3 , 4 ] .
like protein - coding genes , mirna genes are transcribed from the genome mainly from rna polymerase ii ( reviewed in ) .
to date , more than 1000 mirna genes have been identified in humans and 750 in mice , some of which are specifically expressed in the brain [ 610 ] . in the cytoplasm ,
the endonuclease dicer cleaves mirna precursors ( approximately 70 nucleotides in length ) to generate mature ( approximately 21 nucleotides in length ) double - stranded rnas .
these are loaded as single - stranded rnas into the rna - induced silencing complex ( risc ) , composed of argonaute ( ago ) proteins , to negatively regulate gene expression , albeit some exceptions have been documented [ 11 , 12 ] .
this regulation is achieved through binding with imperfect complementarity mainly to the 3 untranslated region ( 3utr ) of target messenger rnas ( mrnas ) , leading to translation inhibition or degradation . both in vitro and in vivo studies
have shown that alterations of a single mirna ( or mirna family ) could have profound effects on hundreds of target genes [ 13 , 14 ] , thus possibly implicating multiple biological pathways .
abnormal phosphorylation and insoluble deposition of tau are observed in more than 20 neurodegenerative disorders , collectively known as tauopathies ( reviewed in ) . in alzheimer 's disease ( ad ) ,
the most common tauopathy , hyperphosphorylated tau accumulates in the somatodendritic compartment of neurons , aggregates , and finally forms neurofibrillary tangles ( nfts ) .
other tauopathies include frontotemporal lobar degeneration ( ftld ) , pick 's disease , progressive supranuclear palsy ( psp ) , corticobasal degeneration ( cbd ) , and progressive aphasia , all of which are characterized by neuronal and/or glial tau inclusions .
although the exact physiological role of tau remains under scrutiny , it is proposed to function to promote microtubule assembly , stabilization , spacing , and parallel - ordered organization , which are necessary for axonal transport and neurite outgrowth ( reviewed in ) .
tau binds to several proteins ( reviewed in ) and therefore could participate in various other paradigms , including targeting the src kinase fyn to dendrites . in the central nervous system ,
tau is expressed as six isoforms , resulting from inclusion or exclusion of alternative exons 2 , 3 , and 10   ( reviewed in ) .
mutations in or surrounding tau exon 10 , leading to an imbalance in tau isoforms with 3 or 4 microtubule - binding domains , can cause familial ftld-17 .
changes in tau isoforms have also been observed in various other tauopathies , including psp and pick 's disease or myotonic dystrophy ( reviewed in ) ; however , the underlying mechanisms involved in abnormal tau splicing and neurodegeneration remain ill - defined . moreover , whether splicing abnormalities function upstream or concomitantly with tau hyperphosphorylation to promote neurodegeneration remains an open debate . to date , several groups have identified factors involved in the regulation of tau splicing .
these include regulatory sequences ( cis - elements ) within or around tau exon 10 as well as specific regulatory proteins ( trans - acting factors ) ( reviewed in ) .
similarly , a number of enzymes have been proposed to regulate tau phosphorylation ( reviewed in ) .
although these studies have been insightful , they were mostly based on artificial and/or overexpression paradigms , which makes it difficult to extrapolate these observations to endogenous tau . in 2006 ,
.   showed a remarkable enhancement of tau - mediated cell death in drosophila cells upon suppression of mirna maturation .
specifically , the authors showed that retinal degeneration caused by the expression of normal or mutant ( r406w ) human tau in vivo was enhanced by loss of r3d1/loquacious , a double - stranded rna binding protein that is required for the activity of dcr-1 ( dicer homologue ) in mirna processing .
interestingly , upregulation of bantam suppressed tau - induced degeneration , suggesting that this mirna could mitigate tau - induced neurotoxicity .
however , as bantam is not conserved in humans , it is tempting to speculate that other mirnas play a similar role in the mammalian brain .
more recently , a neuronal mirna , mir-128 , was shown to modulate the expression of bag2 , a cochaperone potentially involved in tau degradation and aggregation in cultured cos-7 cells and in primary neurons .
our recently published data indicate that conditional knockout ( cko ) of dicer ( resulting in a global reduction in mirna production ) in the adult mouse brain results in disease - like hyperphosphorylation of endogenous tau . moreover , the dicer mutant mice display changes in tau exon 10 splicing , as seen in various tauopathies including psp and pick 's disease . in this paper
, we highlight salient observations with regard to these studies and highlight outstanding questions related to mirna research in tauopathies .
tau is a phosphoprotein that contains more than 80 potential phosphorylation sites ( reviewed in ) .
it is generally well accepted that tau phosphorylation is important for microtubule binding , whereas phosphorylation causes tau to detach from microtubules .
hyperphosphorylation , defined as increased phosphorylation of physiological sites and additional phosphorylation at pathological sites , characterizes insoluble aggregates of tau . however , in its unphosphorylated form , under thermal stress , tau localizes to the nucleus , where it protects dna from double - stranded dna damage
. a phosphorylated pool of tau could also localize to somatodendritic compartment as well as the dendritic spine to modulate neuronal plasticity and glutamatergic transmission .
tau phosphorylation is very sensitive to intrinsic and extrinsic changes ( e.g. , heat , cold , stress , and starvation ) [ 2932 ] .
thus , any changes in the delicate balance between the tau kinases and phosphatases could have serious biological consequences , and the identification of these regulatory enzymes in vivo is of particular importance .
it is noteworthy that some of those central key kinases also regulate indirectly tau splicing through phosphorylation of splicing factors [ 3336 ] .
together , deregulation of kinase and/or phosphatase activity could be dually detrimental towards tau splicing and phosphorylation , which synergistically would promote tau aggregation .
as general posttranslational regulation of gene expression , mirnas are potential modulators of kinase , phosphatase , and/or splicing factor expression . while studying the effects of dicer loss in the brain , we observed significant changes in endogenous tau phosphorylation and splicing .
this was demonstrated at the rna and protein levels using , rt - pcr , 2d electrophoresis and tau phospho - specific antibodies .
because of using the cre - loxp system , dicer inactivation was limited to neurons , and in particular postmitotic pyramidal neurons .
it is noteworthy that only a few studies have documented changes in endogenous tau phosphorylation in vivo , as most biological models express exogenous and/or mutated human tau .
remarkably , several phosphoepitopes related to disease , including serine 422 , were increased in the dicer mutant mice when compared with controls .
unfortunately , given the rather quick lethality associated with dicer loss ( approximately 4 weeks ) , we could not determine whether tau hyperphosphorylation concurred before or after neurodegeneration .
nevertheless , these results provide a proof of concept that mirna haploinsufficiency causes abnormal tau hyperphosphorylation and missplicing .
as stated above , several tau kinases and phosphatases have been identified , some of which are believed to contribute significantly to tau hyperphosphorylation in vivo . in attempt to identify such enzymes in the dicer cko mice , we performed whole - genome microarrays and western blot analyses .
these experiments led to the identification of erk1/mapk3 ( and possibly erk2/mapk1 ) as a major regulator of neuronal tau phosphorylation in vivo , at least in this model . in line with this observation
, several other enzymes can potentially contribute to tau phosphorylation misregulation in this and other models , and in particular disease conditions in humans .
in line with this hypothesis , a number of proposed tau kinases , including gsk3 and jnk / mapk8 , are prone to mirna regulation in various cell types [ 37 , 38 ] . nevertheless , it is interesting to observe that erk phosphorylation is increased in tau - positive neurons in ad and other tauopathies [ 3941 ] .
in addition , erk is essential for brain development and involved in neuronal death [ 42 , 43 ] .
specific gene knockout mouse models are required to assess the role of these proteins in the regulation of tau phosphorylation and neurodegeneration in vivo .
although it is a conceptually crude experimental approach , the dicer cko mice provide a unique and unbiased model to study global mirna function in the brain .
to identify mirnas involved in the regulation of erk1 ( and consequently tau phosphorylation ) , we used several prediction programs that are available online , including targetscan ( http://targetscan.org/ ) .
this program identified a number of potential mirna - binding sites in the 3utr of erk1 .
our functional assays provided the validation that several members of the mir-16 family ( mir-16 , -15 , -195 , -497 ) could directly modulate endogenous erk1 and tau phosphorylation in neuronal cells in vitro , including rat primary neurons .
of mention , both endogenous mir-16 and tau are enriched in distal axons of sympathetic neurons .
intriguingly , mir-15a and mir-15b are downregulated in ad brain and cerebrospinal fluid , respectively [ 25 , 45 , 46 ] , providing clinical relevance for these observations .
moreover , mir-15 targets the proapoptotic protein bcl-2 , whose protein levels are increased in ad [ 4749 ] .
in addition , mir-16 overexpression could regulate app expression in vivo in the mouse brain .
taken together , these observations highlight the potential importance of the mir-16 family in ad development by regulating cell survival , amyloid production , and tau phosphorylation ( figure 1 ) . interestingly , targetscan predicts more than 1000 human target genes for mir-16 , several of which are associated with networks related to cell death , cellular organization , and molecular transport ( s. s. hbert , unpublished observations ) .
notably , among the high - scoring predicted targets are mirna - processing regulators such as tnrc6b
. it will be interesting to see whether loss of mir-16 family members in vivo recapitulates , at least in past , the observed effects on erk and , most importantly , tau phosphorylation in vivo .
it is interesting to note that dicer deficiency in the adult brain is also associated with changes in tau splicing . using a similar strategy as above ( e.g. , bioinformatics , microarrays , literature search , western blot analysis , etc . ) , we identified mir-132 and the neuronal splicing regulator ptbp2 as potential regulators of endogenous tau exon 10 splicing in neurons .
these results are consistent with previous findings linking tau exon 10 splicing regulation by ptbp1 in vitro .
while not discussed in detail in our study , other mirnas , including mir-124 and mir-9 , could also regulate endogenous tau exon 10 splicing in neuronal cells by targeting specific regulatory and/or splicing factors .
both mirnas are downregulated in ad [ 5658 ] , which could have important consequences for tau metabolism , at least in certain biological contexts ( figure 1 ) .
for instance , downregulation of mir-9 is observed in the presence of exogenous a in mouse primary neurons . whether this or other mirnas function as intermediates between a peptides , tau missplicing and hyperphosphorylation remain an exciting possibility .
interestingly , differential splicing of the tau transcript has also been reported in ad [ 60 , 61 ] .
psp is a cause of late - onset atypical parkinsonism described by steele et al . .
are mainly composed of tau with 4 microtubule - binding domains ( 4r - tau ) [ 13 , 15 ] . using psp as a model disease , we identified mir-132 to be selectively downregulated in pathological conditions .
interestingly , ptbp2 protein ( but not mrna ) levels were increased in psp patients and correlated significantly with mir-132 expression .
these experiments provide unprecedented molecular links among abnormal tau splicing , hyperphosphorylation , and sporadic tauopathies .
interestingly , changes in ptbp1 and ptbp2 levels , and by extension alternative splicing patterns , have been documented in human diseases , including neurodegenerative disorders [ 63 , 64 ] . on the basis of these observations ,
it is tempting to speculate that mirnas could contribute significantly to several aspects of tau metabolism and neuronal dysfunction in various diseases .
for instance , what are the biological and clinical significance of these findings ? are other mirnas involved in tau metabolism regulation ? can mirnas be used as diagnostic and possibly therapeutic agents for sporadic tauopathies ? without a doubt , these and other questions will require extensive followup studies in various models , from cells to animals to humans .
abnormal regulation of tau phosphorylation and/or alternative splicing is associated with the development of a large ( > 20 ) group of neurodegenerative disorders collectively known as tauopathies , the most common being alzheimer 's disease . despite intensive research , 
 little is known about the molecular mechanisms that participate in the transcriptional and posttranscriptional regulation of endogenous tau , especially in neurons . 
 recently , we showed that mice lacking dicer in the forebrain displayed progressive neurodegeneration accompanied by disease - like changes in tau phosphorylation and splicing . 
 dicer is a key enzyme in the biogenesis of micrornas ( mirnas ) , small noncoding rnas that function as part of the rna - induced silencing complex ( risc ) to repress gene expression at the posttranscriptional level . 
 we identified mir-16 and mir-132 as putative endogenous modulators of neuronal tau phosphorylation and tau exon 10 splicing , respectively . 
 interestingly , these mirnas have been implicated in cell survival and function , whereas changes in mir-16/132 levels correlate with tau pathology in human neurodegenerative disorders . 
 thus , understanding how mirna networks influence tau metabolism and possibly other biological systems might provide important clues into the molecular causes of tauopathies , particularly the more common but less understood sporadic forms .