MicroRNAs in neurodegeneration.
ABSTRACT microRNAs (miRNAs) act as post-transcriptional regulators of gene expression in diverse cellular and developmental processes. Many miRNAs are expressed specifically in the central nervous system, where they have roles in differentiation, neuronal survival, and potentially also in plasticity and learning. The absence of miRNAs in a variety of specific postmitotic neurons can lead to progressive loss of these neurons and behavioral defects reminiscent of the phenotypes seen in the pathologies of neurodegenerative diseases. Here, we review recent studies which provide a link between miRNA function and neurodegeneration. We also discuss evidence which might suggest involvement of miRNAs in the emergence or progression of neurodegenerative diseases.
- SourceAvailable from: Gracjan Patryk Michlewski[Show abstract] [Hide abstract]
ABSTRACT: microRNAs shape the identity and function of cells by regulating gene expression. It is known that brain-specific miR-9 is controlled transcriptionally; however, it is unknown whether post-transcriptional processes contribute to establishing its levels. Here we show that miR-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation of the embryonic carcinoma cell line P19. We demonstrate that miR-9 is more efficiently processed in differentiated than in undifferentiated cells. We reveal that Lin28a affects miR-9 by inducing the degradation of its precursor through a uridylation-independent mechanism. Furthermore, we show that constitutively expressed untagged but not GFP-tagged Lin28a decreases differentiation capacity of P19 cells, which coincides with reduced miR-9 levels. Finally, using an inducible system we demonstrate that Lin28a can also reduce miR-9 levels in differentiated P19 cells. Together, our results shed light on the role of Lin28a in neuronal differentiation and increase our understanding of the mechanisms regulating the level of brain-specific microRNAs.Nature Communications 04/2014; 5:3687. · 10.74 Impact Factor
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ABSTRACT: Neurodegenerative diseases are characterized by the loss of specific neuronal populations. Epidemiological studies and pathologycal analyses have demonstrated the existence of a link between mutations in specific genes and heritable forms of neurodegenerative diseases. Although some of these mutations can be found in higher frequency among certain ethnic populations, together they account for only a small percentage of all cases. Therefore, at the present it is well accepted that the causes of idiopathic or non-familial forms of neurodegenerative diseases are multifactorial, including genetic predisposition, epigenetic factors, age, and even environmental factors. Although the key molecular and cellular events underlying the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and multiple sclerosis, are clearly different, a common feature between them is neuroinflammation. In this context, the central nervous system has long been considered to be an immuneprivileged site because of the presence of the blood–brain barrier and the lack of a lymphatic system, still it is now well established that it is fully capable of mounting an inflammatory response. Invading pathogens, trauma, stroke, intraneural as well as extracellular fibrillary material can trigger local invasion of circulating immune cells, production of reactive oxygen and nitrogen species, as well as the activation of the brain resident macrophages known as microglia. Inflammation in the central nervous system has been appropriately described as a two-edged sword; in acute situations inflammatory mechanisms limit injury and promotes healing; however, in a chronic situation neuroinflammation can seriously damage viable host tissue. Current studies support the notion that neuroinflammation promotes or facilitates neurodegeneration; therefore, early intervention with antiinflammatory therapies in populations identified to be at risk due to genetic mutations may represent a valuable tool. We present recent data regarding non-genetic mechanisms that regulate the development of neurological disorders including Huntington’s disease, multiple sclerosis, Parkinson’s disease and Alzheimer’s disease.Molecular Aspects of Inflammation, 11/2013: chapter Neurodegenerative disorders and inflammation: pages 173-207; Research Signpost., ISBN: 978-81-308-0528-3
Available online at www.sciencedirect.com
microRNAs in neurodegeneration
Natascha Bushati and Stephen M Cohen
microRNAs (miRNAs) act as post-transcriptional regulators of
gene expression in diverse cellular and developmental
processes. Many miRNAs are expressed specifically in the
neuronal survival, and potentially also in plasticity and
learning. The absence of miRNAs in a variety of specific
postmitotic neurons can lead to progressive loss of these
neurons and behavioral defects reminiscent of the phenotypes
seen in the pathologies of neurodegenerative diseases.
Here, we review recent studies which provide a link
between miRNA function and neurodegeneration. We also
discuss evidence which might suggest involvement of miRNAs
in the emergence or progression of neurodegenerative
Temasek Life Sciences Laboratory, 1 Research Link, Singapore 117604,
Corresponding author: Cohen, Stephen M (Steve@tll.org.sg)
Current Opinion in Neurobiology 2008, 18:292–296
This review comes from a themed issue on
Edited by Carlos Ibanez and Michael Ha ¨usser
Available online 5th August 2008
0959-4388/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
What is neurodegeneration?
The term neurodegeneration covers a broad spectrum of
defects, with diverse causes; it describes the process of
nerve cells losing their structure and function. Neurode-
generative diseases are pathologies that directly affect
specific subsets of neurons. The hallmarks of these dis-
eases are neuronal dysfunction, progressive degeneration,
and progressive neuronal loss. Age is the most prominent
risk factor for developing a neurodegenerative disease.
However, for many of the hundreds of ‘sporadic’ neuro-
degenerative disorders, rare genetic predispositions have
been identified: carriers of these alleles can pass on the
disease and their offspring are at risk of developing an
early onset form of the disease. Purely familial neurode-
generative disorders include those caused by proteins
containing polyglutamine (polyQ) stretches, which are
expanded in the pathogenic allele, for example in Hun-
tington’s disease. To date, the best-studied neurodegen-
Parkinson’s disease (PD), Huntington’s disease (HD),
and amyotrophic lateral sclerosis (ALS).
Neurodegeneration has been studied in animal models,
including different transgenic mouse models and heter-
ologous systems using human polyQ-repeat proteins in
Drosophila [1,2]. From such studies, many cellular pro-
cesses have been implicated in neurodegenerative dis-
orders, including the formation of atypical protein
assemblies, neuronal death, protein degradation, and
What are microRNAs?
microRNAs (miRNAs) are a class of endogenous, small
noncoding RNAs. Some of them are conserved in both
their sequence and expression patterns across a wide
range of animals. miRNAs are loaded onto the RNA-
induced silencing complex, RISC, and guide this com-
plex to their target mRNAs via base-pairing interactions.
6–7 nts at the 50end of the miRNA, the so-called ‘seed
sequence’, are thought to determine most of their target
specificity. An Argonaute (Ago) protein is the catalytic
component of the RISC complex, and depending on the
type of Argonaute present and the degree of complemen-
tarity between the miRNA and its target sequence, the
target mRNA may be endonucleolytically cleaved and
degraded or translationally repressed. Translational
repression often brings about target mRNA degradation
via decapping and subsequent exonucleolytic degra-
dation (reviewed in ). Recent reports also indicate that
miRNAs can upregulate their targets [4,5].
The average miRNA is predicted to be able to act on
target sites in hundreds of genes, so each miRNA has the
potential to regulate a large number of mRNA targets
(reviewed in ). Therefore, if a miRNA is expressed at
aberrant levels, either higher or lower than normal, the
expression of many genes could be perturbed. Possible
target genes often include regulatory factors, so the
transcriptional profile of a cell expressing a miRNA at
nonphysiological levels might be altered extensively.
miRNAs have been shown to be involved in diverse
cellular and developmental processes, and some specific
miRNAs have been implicated in disease (reviewed in
Many microRNAs are specifically expressed
and required in the brain
Many miRNAs are expressed in the central nervous
system, often in a temporally and/or spatially regulated
than 400 miRNAs have been identified in human and
Current Opinion in Neurobiology 2008, 18:292–296www.sciencedirect.com
chimpanzee brain [8,9?], and it is estimated that ?1000
miRNAs are expressed in the human brain [9?]. Inter-
estingly, many miRNAs expressed in the human brain
are not conserved beyond primates, suggesting a recent
origin [9?]. Although functions have been assigned to
only very few of these brain-specific miRNAs, evidence
is beginning to accumulate for roles in normal develop-
ment, differentiation, and functions as well as roles in
miRNAs have been shown to be essential for the de-
velopment of the zebrafish nervous system and brain
morphology . Mouse dicer mutants, which are
impaired in miRNA biogenesis and therefore do not
produce mature, functional miRNAs, die before neurula-
tion . However, conditional removal of Dicer from
various mouse neuronal cell types has demonstrated that
miRNAs have roles in neuronal survival during develop-
ment and in mature neurons [14?,15–18]. In cultured
hippocampal neurons, miR-134 was shown to be involved
in dendritic spine morphology by regulating Limk1
expression . In chick embryos, antisense-mediated
depletion indicates a role for the highly conserved, CNS-
specific, miR-124 in neuronal differentiation and main-
tenance of neural identity [20,21]. The requirement of
miR-124 for neural differentiation has also been demon-
strated in mouse cell lines . In C. elegans, miRNAs are
required for the correct specification and maintenance of
two asymmetric gustatory neurons via a double negative
feedback loop [23,24]. In Drosophila, miR-7 maintains the
differentiated state of photoreceptors, also via a feedback
loop . Moreover, miRNAs and/or other small RNAs
seem to be involved in synaptic plasticity and learning by
translationally repressing their localized mRNA targets at
the synapse . The variety of these studies demon-
strates the diversity of miRNA functions in the central
miRNAs and neurodegenerative disease:
Midbrain dopaminergic neurons (DNs) of the substantia
nigra are lost in PD. Depletion of Dicer to block miRNA
biogenesis was observed to lead to a reduction in the
ability of ES cells to differentiate into midbrain DN [14?].
The idea that miRNAs are involved gained support from
the finding that DN differentiation could be partially
containing miRNAs, isolated from the embryonic mouse
midbrain. Consistently, specific deletion of Dicer in
mouse midbrain DNs led to increased apoptosis and
neurodegeneration. Midbrain DNs were progressively
lost, until 90% of these cells in the substantia nigra had
died. The animals displayed reduced locomotion remi-
niscent of the motility problems seen in PD [14?].
Together, these observations raise the possibility that
loss of miRNAs might be involved in the emergence
and/or progression of PD.
Interestingly, certain midbrain-enriched miRNAs have
been found to show altered expression in Parkinson’s
samples. miR-133b was deficient in PD midbrain samples
and in aphakia mice, a naturally occurring mouse mutant,
which can be used as a model of neuronal loss in human
box transcription factor required for the survival of DNs
and for motor activity . Polymorphisms in Pitx3 have
been associated with PD in humans [28,29].
miR-133b and Pitx3 form a negative feedback loop: Pitx3
induces miR-133b transcription, which in turn represses
inthePD model. An important, butunanswered question,
is whether the loss of the miRNA contributes to the
etiology of PD. This has not been addressed directly in
the mouse model because mutants lacking miR-133b are
vitro DN differentiation assay led to increased expression
of DN markers, suggesting enhanced DN differentiation.
Conversely overexpression of the miRNA targeted pitx3
expression is lost in PD samples, these findings indicate
that miR-133b cannot be the miRNA responsible for the
ES cell Dicer phenotype or the progressive loss of mouse
miR-133b. The miRNA(s) carrying protective potential
against DN neurodegeneration remain to be identified.
This profound loss of DNs of the substantia nigra con-
trasts with results of a study where Dicer was removed
from the dopaminoceptive neurons of the striatum . A
range of phenotypes was observed, including reduction of
the size of the brain and of neurons, ataxia, wasting, and
premature death, but the dopaminoceptive neurons sur-
vived throughout the animal’s life. Therefore, Dicer does
in all postmitotic neurons, as Dicer is also dispensable in
mature olfactory neurons . The observed phenotypes
are reminiscent of mouse models of the Rett syndrome, a
neurodevelopmental disorder. Notably, dysfunction, but
not necessarily extensive loss, of dopaminoceptive
neurons has also been implicated in PD .
The majority of AD cases arise sporadically. All share an
underlying common molecular defect, accumulation of
the Ab peptide, but their etiology is unknown. Ab pep-
tide is produced by the cleavage of the amyloid precursor
Increased levels of BACE1/b-secretase are linked to
Ab accumulation and AD pathology, and therefore might
serve as a risk factor for sporadic AD .
In ?30% of sporadic AD patient samples, BACE1 protein
levels are significantly increased, though its mRNA levels
microRNAs in neurodegeneration Bushati and Cohen293
Current Opinion in Neurobiology 2008, 18:292–296
are unchanged. Several miRNAs are expressed at altered
levels in AD samples, and some of these have target sites
in the BACE1 30UTR [33?]. The miR-29a-1 and miR-
29b-1 cluster is strongly downregulated in these AD
samples. During normal brain development, miR-29a/
b-1 and BACE1 protein are expressed in a temporally
reciprocal manner, a phenomenon observed frequently
for miRNA–target relationships during development .
In HeLa cells, both miRNAs were able to repress expres-
sion of a luciferase reporter carrying the BACE1 30UTR,
but not of a control reporter in which the conserved target
sites were mutated [33?]. Upon overexpression of miR-
29a/b-1 in HEK293 cells, endogenous BACE1 levels and
the levels of BACE1 cleavage products, including Ab
peptide, were downregulated. Conversely, depletion of
endogenous miR-29a/b-1 from these cells led to the
accumulation of Ab production. Taken together, reduced
levels of miR-29a/b-1 might contribute to Ab accumu-
lation and AD pathology in sporadic AD due to reduced
miR-29a/b-1 mediated suppression of BACE1 protein
miRNAs and polyQ-repeat expansion
Expansion of the polyQ repeats in the Spinocerebellar
ataxia type 3 (SCA3) protein Ataxin-3 has been linked to
neurodegeneration . Depletion of dicer in HeLa cells
significantly enhanced pathogenic Ataxin-3 induced
toxicity , which could be partially rescued by com-
plementing the cells with the purified small RNA fraction
containing total HeLa cell miRNAs. Which miRNAs
have a protective role in SCA3, and if these are down-
regulated in affected individuals, remains to be deter-
The polyQ expansion disorder Spinocerebellar ataxia
type 1 (SCA1) is characterized by the death of cerebellar
Purkinje cells . Depletion of Dicer from mouse Pur-
kinje neurons did not impair cell function and survival in
young mice (eight-week-old). However, in 13-week-old
mice, the Purkinje neurons progressively degenerated
and cell death started to occur. At the same age, the mice
developed a slight tremor and mild ataxia, both of which
became more severe with advancing age . As in the
case of SCA3, the miRNAs seem to have a protective
function. However, whether the lack of miRNAs, and not
an unrelated Dicer function, causes these phenotypes
remains to be demonstrated.
Drosophila miR-8 and Atrophin — a connection to
The polyQ repeat of human Atrophin-1 is expanded in
individuals with dentatorubral-pallidoluysian atrophy
(DRPLA), resulting in neuronal apoptosis. Although
there is not yet evidence for a direct connection between
miRNAs and DRPLA, analysis of the conserved Droso-
phila miRNA miR-8 has suggested that this may be
worth exploring. miR-8 sets the levels of Drosophila
Atrophin by binding to its 30UTR [36?]. miR-8 carries
the same seed sequence as mouse and human miR-200b
and miR-429. Flies depleted of miR-8 display elevated
levels of apoptosis in the brain and perform poorly in a
declines more rapidly with age than that of control flies.
Both phenotypes are partially rescued by limiting the
degree to which Atrophin can be upregulated, indicating
that elevated Atrophin levels are responsible for the
Drosophila Atrophin carries two polyQ stretches [37,38],
and several miR-8-binding sites are present in the atro-
phin 30UTR [36?]. Interestingly, the gene seems to have
diverged in mammals, where Atrophin-1 carries a polyQ
stretch, but no miR-200b/miR-429
[36?,37,38]. The other mammalian Atrophin ortholog,
RERE, does not contain a polyQ region, but has func-
tional miR-200b/miR-429 binding sites.
Expansion of the polyQ stretch is necessary, but not
sufficient to cause pathology . Moreover, high levels
of a human wildtype (unexpanded) polyQ protein can
lead to degenerative phenotypes in flies and mice .
This and other studies suggest that the pathogenic
protein functions within its endogenous pathways, and
not merely through the polyQ expansion [34,39,40]. It
therefore seems plausible that release of miR-8-mediated
repression of fly Atrophin, even in the absence of a polyQ
expansion, induces a phenotype that might correspond to
the disease phenotype seen with human polyQ expanded
miR-8 phenotype requires the presence of the polyQ
stretch in fly Atrophin. It would also be interesting to
know whether human RERE, which contains miR-200b/
miR-429 binding sites but no polyQ stretch, carries neu-
rodegenerative potential. Would expression of human
RERE in miR-8 expressing cells in Drosophila cause
neurodegeneration, as seen for Drosophila Atrophin?
patients samples might also provide evidence to whether
these miRNAs are involved in the disease, potentially
through their ability to regulate RERE. Since RERE has
been shown to bind Atrophin-1  and induce apoptosis
upon overexpression , the regulation of RERE via its
miRNA sites could reflect a conserved neuroprotective
function of themiR-8/miR-200b/miR-429
Recently, depletion of all miR-200 family miRNAs was
shown to impede terminal differentiation and induce
apoptosis of olfactory progenitors in zebrafish . How-
ever, in the mature olfactory neurons, miRNAs are dis-
pensable . Whether or not miRNAs are needed to
prevent neurodegeneration depends on the type of
Current Opinion in Neurobiology 2008, 18:292–296 www.sciencedirect.com
To date, it remains uncertain whether miRNAs are
actively involved in the etiology or progression of neu-
rodegenerative disorders. These small regulators clearly
seem to be required for the survival of specific types of
mature neurons in some model organisms, but whether
loss of individual miRNAs can account for the drastic
disease phenotypes remains to be determined. Because
many different cellular processes have been implicated in
neurodegenerative disorders, miRNAs involved in these
pathways will obviously be found to be misregulated in
disease tissues. However, the degree to which their mis-
regulation is causative in the diseases remains a pressing,
but unanswered, question. Identification of causal links,
opens the prospect for therapeutic intervention, perhaps
by replacing missing miRNAs, or blocking the activity of
overexpressed ones. Likewise some miRNAs seem to
have a neuroprotective role, and therefore could poten-
tially be used to prevent or at least decelerate the pro-
gressive loss of neurons in the diseased brain. These are
tantalizing prospects, but still far from our grasp.
We thank Ville Hietakangas for helpful comments on the manuscript. This
work was supported by EU-FP6 grant ‘Sirocco’ LSHG-CT-2006-037900
and by the Temasek Life Sciences Laboratory.
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