Journal Pre-proof

Role of microRNAs in neurodegeneration induced by environmental

neurotoxicants and aging

Tanisha Singh, Sanjay Yadav

PII: S1568-1637(19)30387-3
DOI: https://doi.org/10.1016/j.arr.2020.101068
Reference: ARR 101068

To appear in: Ageing Research Reviews

Received Date: 23 October 2019

Revised Date: 2 March 2020
Accepted Date: 4 April 2020

Please cite this article as: Singh T, Yadav S, Role of microRNAs in neurodegeneration
induced by environmental neurotoxicants and aging, Ageing Research Reviews (2020),
doi: https://doi.org/10.1016/j.arr.2020.101068

This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.

© 2020 Published by Elsevier.

 Role of microRNAs in neurodegeneration induced by environmental
neurotoxicants and aging
Tanisha Singh1&2 & Sanjay Yadav1&3*

1.
Developmental Toxicology Division, Systems Toxicology and Health Risk Assessment Group, CSIR-
Indian Institute of Toxicology Research (CSIR-IITR); Vishvigyan Bhawan,31 Mahatma Gandhi Marg,
Lucknow-226001, Uttar Pradesh, India, 2Department of Neurological Surgery, School of Medicine,
University of Pittsburgh, 200 Lothrop Street, Pittsburgh, Pennsylvania-15213, USA.3.Department of
Biochemistry, All India Institute of Medical Sciences (AIIMS), Raebareli, Munsiganj, Raebareli-229405,
UP, India

of
*
Corresponding Author

ro
Sanjay Yadav (Ph.D.)
Department of Biochemistry
All India Institute of Medical Sciences, Raebareli

-p
Munsiganj, Raebareli-229405, UP, India.
Ph. No. +91-535-2704400
Email: sanjayitrc@gmail.com
re
Email list of authors:
Tanisha Singh: tanishasingh186@gmail.com
lP
na

Graphical abstract
ur
Jo
 of
ro
Highlights:


-p
Aging emerged as the most protuberant risk factor in developing the neurodegenerative disease
re
by causing non-pathological molecular changes like oxidative status imbalance, impaired
mitochondrial function, increased inflammation, disturbed proteostasis, and deregulated
protein levels.
lP

 Neurotoxicants are any chemical, biological, and physical agents that alter the regular activity
of the nervous system leading to neurodegenerative diseases.
 Alterations in expression of mRNAs through regulatory RNA molecules known as microRNAs
(miRNAs) have emerged as a molecular mechanism regulating aging and neurotoxicant
na

induced degeneration of brain cells.

 Significant miRNAs are known to regulate both aging and neurotoxicant induced
neurodegeneration are miR-34, which targets P53,SIRT1&PARKIN , miR-29 in VDAC1,P53
& BACE1 and miR-126 in Insulin/IGF-1/phosphatidylinositol-3-kinase (PI3K)/AKT
ur

associated pathways.
 Identification of miRNAs, common in aging and neurotoxicant induced neurodegeneration,
will help in understanding the molecular mechanism of neurodegenerative disease.
Jo

Abstract

The progressive loss of neuronal structure and functions resulting in the death of neurons is considered as
neurodegeneration. Environmental toxicants induced degeneration of neurons is accelerated with aging. In
adult brains, most of the neurons are post-mitotic, and their loss results in the development of diseases like
amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's
disease (HD). Neurodegenerative diseases have several similarities at the sub-cellular and molecular levels,
such as synaptic degeneration, oxidative stress, inflammation, and cognitive decline, which are also known
in brain aging. Identification of these similarities at the molecular level offers hope for the development of
new therapeutics to ameliorate all neurodegenerative diseases simultaneously. Aging is known as the most
strongly associated additive factor in the pathogenesis of neurodegenerative diseases. Studies carried out
so far identified several genes, which are responsible for selective degeneration of neurons in different
neurodegenerative diseases. Countless efforts have been made in identifying therapeutics for
neurodegenerative diseases; however, the discovery of effective therapy remains elusive. Findings made in
the last two decades identified microRNAs (miRNAs) as the most potent post-transcription regulatory RNA
molecule, which can condition protein levels in the cell and tissue-specific manner. Identification of
miRNAs, which regulate both neurotoxicant and aging-associated degeneration of brain cells, raises the
possibility that roads leading to aging and neurotoxicant induced neurodegeneration cross at some point.
Identification of miRNAs, which are common to aging and neurotoxicant induced neurodegeneration, will

of
help in understanding the complex mechanism of neurodegenerative disease development. In the future,
the use of natural miRNAs in vivo in therapy will be able to tackle several issues of aging and
neurodegeneration. In the present review, we have provided a summary of findings made on the role of

ro
miRNAs in neurodegeneration and explored the common link made by miRNAs between aging and
neurotoxicants induced neurodegeneration.

Keywords: Aging, Neurotoxicants, microRNA, Neurodegeneration

-p
re
1. Introduction

The increased lifespan of humans in the past few decades due to improvement in health services and
lP

awareness about nutrition and hygiene has substantially increased the portion of the aged population in our
society [1]. Age-associated health issues are challenges for society, and researchers have to find new ways
to reduce the health issues associated with the aged population. After completing the first three-four quarters
of life, secondary metabolic products start accumulating, and the aging phenotype starts affecting the
na

physiological systems. The brain is known as the most severely affected organ by aging. Aging occurs due
to impairment in the oxidative system, which results in the formation of an infinite amount of reactive
oxygen species (ROS). Impairment of the oxidative system is reported in both the aging brain and
neurodegenerative diseases [2]. Neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's
ur

disease (AD), Huntington disease (HD), and Amyotrophic lateral sclerosis (ALS) are age-associated and
late-onset diseases, which aggravates with increasing age. Imbalance of oxidative status is one of the
standard features of neurodegenerative diseases. Deregulation of proteins required for mitochondrial
Jo

functions or antioxidant systems leads to an oxidative imbalance in cells, which also takes place in aging
[3, 4]. Moreover, it is demonstrated by several studies that exposure to toxicants during early development
has substantial effects on the pathogenesis of neurodegenerative diseases at a later age [5]. In spite of
several studies carried out on the mechanism of neurodegeneration, still, the reason behind selective
degeneration of neurons is not known. Formation of misfolded proteins and aggregates is a common feature
in all neurodegenerative diseases; however, still triggering agent of protein misfolding is not identified.

The emergence of regulatory RNA molecules in the 21st century sheds light on the mechanism of
neurodegeneration and raised promise towards the identification of triggering events of neurodegenerative
diseases. The discovery of regulatory RNA molecules has opened a new window to look at cellular and
molecular mechanisms of neurodegeneration. Regulatory RNA molecules are mostly non-coding RNAs
(NCR), which do not code for proteins. The small NCRs, which are transcribed as a stem-loop structure
and binds in a sequence-specific manner at 3'-UTR of mRNAs, are termed as microRNAs (miRNAs).
Identification of miRNAs has significantly increased our understanding of post-transcriptional regulation
of gene expression and provided a new tool for developing gene-based therapeutics of complex diseases [6,
7]. Studies carried out in the last decade have identified the crucial role of miRNAs in almost every cellular
process; however, studies have shown their dominant role in development, cancer, and neurodegeneration
[8-12]. The recent opinion gives hope on miRNAs in moderating the aging system by potentially modulate
knowledge into antiaging inferences that target cellular senescence. The various approach provides
information that change in miRNA structure as well as in delivery systems, results in antiaging interventions
[13]. Identification of RNA molecules, which regulates aging-induced neurodegeneration and
neurotoxicant induced neurodegeneration raises hope for the development of new therapeutics of

of
neurological disorders. Mapping the cellular and molecular pathways of neurodegeneration will further
assist in revealing the mechanism of selective degeneration of neurons in different neurological disorders.

ro
In the present review, we have made attempts to understand the mechanism of neurodegeneration focusing
on miRNAs, which are regulatory RNA molecules and can be a connecting link between neurodegeneration
induced by environmental exposure and aging.

2. MicroRNAs: Non-coding Regulatory RNA molecules

-p
re
MiRNAs are a class of non-coding RNA molecules acquired during the evolution of multicellular
organisms to cope up with specialized functions of different types of cells in multicellular and complex
lP

organisms [14]. In the year 2000, miRNAs were first identified for their role in controlling the
developmental timing of Caenorhabditis elegans [15, 16]. Presently, miRNAs are demonstrated to regulate
the expression of genes related to almost every cellular event, including proliferation, differentiation,
migration, and apoptosis [14, 17-19]. To date, more than 2500 miRNAs have been identified and
na

characterized in humans with sequence details [20]. Mature miRNAs are single-stranded, small (approx.
22nt in length) in length, which binds at complementary sequences present at 3’-UTR of protein-coding
mRNAs and negatively regulates protein synthesis [20]. MiRNAs are transcribed by RNA polymerase II
either from inter or intragenic regions, and initial transcripts are known as primary-miRNA (pri-miRNA).
ur

Pri-miRNA is folded into a stem-loop structure, which is cleaved by a complex of riboendonuclease

enzymes, Drosha, and DGCR8 protein into a 70-80nt hairpin structure called precursor-miRNA (pre-
miRNA). The hairpin loop structure (pre-miRNA) formed in the nucleus is transported to the cytoplasm via
Jo

the Ran-GTP dependent mechanism by exportin-5, where it gets cleaved by RNase III-enzyme named Dicer
and TAR RNA- binding protein 2 (TRBP), which creates a short duplex RNA of 22 nucleotides. The newly
born short RNA duplex binds with a protein called Argonaute forming a complex named miRNA-induced
silencing complex (miRISC complex). Out of two strands of the duplex, one is a passenger strand or
miRNA*, and the other one is guide strand or mature (usually dominant and functional) miRNA. RISC
controls gene expression by binding at the 3′UTR of target mRNAs leading to degradation of mRNAs or
translational repression of protein expression. Overall, miRNAs provide an extra level of regulation in
protein synthesis, which is dependent on the complementarity of sequence between seed sequence of
miRNAs and 3'UTR of target mRNAs [20, 21].
 3. Neurotoxicant induced regulation of miRNAs

Neurotoxicity refers to abnormal activity of the brain in response to toxic agents, whether they are natural
or human-made synthetic chemicals. Administration of substances such as metals, solvents, pesticides,
which potentially induce neuronal damage or neurodegeneration, are few examples of neurotoxicants [22].
It is firmly believed that environmental constituent such as metals, pollutants, pesticides, and somewhere
lifestyle plays a crucial role in brain health, either direct or in an indirect manner [23]. Unfavorable changes
in the structure/function of the nervous system due to any neurotoxicant profound consequences of
neurological, behavioral, and related body functions and processes. These toxicants induce morphological
changes such as loss of neurons, degeneration of neuronal axons, loss of myelin and glial cells, along with
neurochemical changes, i.e neurotransmitters release, and inflammatory response. Brain cells are more
susceptible to oxidative stress either during normal aging or due to neurotoxicant induced

of
neurodegenerative diseases [24-27]. As a result of oxidative stress and impaired antioxidant mechanism,
levels of reactive oxygen species (ROS) are elevated in aged or mature neurons [28]. Aging and
neurodegeneration, both results in altered neuronal metabolism [29-32], cognitive impairments [33-35],

ro
impaired calcium signalling [36] , damaged mitochondria [37-41], glutamate receptors alterations [26, 42],
and accumulation of altered aggregated proteins [43-45]. Moreover, it has been reported that aging
significantly increases the vulnerability of neurons to toxicants induced neurodegeneration [46, 47]. There

-p
are various studies that have proven that environmental chemicals and toxicants induced changes in miRNA
expression.The role of miRNAs demonstrated in regulating the protein homeostasis has placed it at the
forefront of new research approaches for developing novel therapeutic targets of neurodegenerative
re
diseases [48, 49]. The brain is identified as one of the richest sources of miRNAs, and studies have shown
dynamic regulation of the miRNAs in developing brain and maturing neurons [18, 19, 50-52]. Expression
of miRNAs in the brain is shown to be regulated by several environmental neurotoxicants like (metal/
lP

pesticides), the drug of abuse (ethanol/ nicotine), and other agents [17, 53-55]. Heavy metals and pesticides
are the most common environmental neurotoxicants, which alters brain structure and functions and induces
neurodegeneration [56-59]. The role of post-transcriptional mechanisms in regulating protein synthesis
(like tyrosine hydroxylase) was demonstrated before the discovery of miRNAs [60, 61]. In 2006, Bilen et
al., were first to show that the expression of miRNAs regulates neurodegeneration [62]. Their studies have
na

explored whether miRNA processing genes can modulate polyglutamine-induced neurodegeneration and
observed that inhibiting miRNA processing enhances polyglutamine-induced neurodegeneration [62].
Dicer (a miRNA maturation enzyme) knockout studies carried out in Purkinje cells have shown that in the
ur

absence of mature miRNAs, the probability of neurodegeneration increased [63]. Studies from our lab have
shown that knocking down the Dicer gene in SH-SY5Y, human neuroblastoma increases its sensitivity
towards ethanol exposure [53]. Our unbiased miRNA profiling studies in SH-SY5Y cells exposed with
acute and chronic dosages of ethanol have identified dramatic changes in miRNA profile. Global miRNA
Jo

profiling has identified miR-497 and miR-302b as two maximally up-regulated miRNAs in SH-SY5Y cells
exposed with ethanol for 72 hours [53]. Increased expression of miR-497 down-regulates BCl2, an anti-
apoptotic protein, which results in increased apoptosis of neuronal cells. Up-regulation of miR-302b
downregulated levels of CyclinD2, a protein known for its role in regulating adult neurogenesis [53].
Sathyan et al., (2007) have also demonstrated the role of miRNAs in determining the survival and
proliferation of neural progenitor cells exposed to ethanol [64]. They have shown that ethanol, at a level
attained by alcoholics, and significantly suppressed the expression of miR-21, miR-335, miR-9, and miR-
153, whereas a lower ethanol concentration, attainable during social drinking, induced expression of miR-
335[64]. Studies of Yuanlin Qi et al., (2014) have also identified the role of miRNAs (miR-29b) in ethanol-
induced neuronal cell death in developing cerebellum[65]. The study of Pietrzykowski AZ et al., (2008),
demonstrated the regulation of calcium- and voltage-activated potassium channel (BK channel), whose
splice variant stability provided by miR-9 underlies neuroadaptation to alcohol [66]. Studies of Wang et al.,
(2008) indicated an important role of miRNAs in development and congenital disabilities in mice. They
observed the up-regulation of miR-10a, miR-10b, miR-9, miR-145, miR-30a-3p and miR-152 and down-
regulation of miR-200a, miR-496, miR-296, miR-30e-5p, miR-362, miR-339, miR-29c and miR-154 in
mice brain which were prenatally exposed to ethanol [67]. Studies of Tal et al., (2012) identified the role
of miR-9/9* and miR-153c, which controls the neurobehavioral development and functions in zebrafish
[68]. Studies of Bahi and Dreyer (2013) shed light on the linkage between striatal miR-124a and BDNF
signaling, which has crucial roles in alcohol consumption [69]. Li et al., (2013) have reported the role of
miR-382 in alcohol-induced addiction and indicated the possibility of using it as novel therapeutic targets

of
for alcoholism [70]. Studies of Lippai Di et al., (2013) have suggested that the role of chronic alcohol-
induced microRNA-155 in neuroinflammation in a TLR4-dependent manner [71]. Zhang et al., (2014)
reported that miR-339-5p inhibits alcohol-induced brain inflammation via regulating the NF-κB pathway

ro
[72]. Recently, studies of Zhang et al., (2015) have shown that prenatal ethanol exposure amends adult
hippocampal VGLUT2 expression with associated changes in miR-467b-5p levels and promotes DNA
methylation and H3K4 trimethylation [73]. Overall, it seems that miRNAs are involved in almost all the

-p
cellular processes affected by ethanol exposure [74-78].

Another class of drugs or psychostimulants like cocaine, morphine, nicotine persuades significant
re
neuroadaptive changes through a surplus of gene regulatory mechanisms leading to addiction. These drugs
or opioids are well known for triggering synaptic plasticity and synaptic remodeling [79-82]. It has been
shown in various reports that along with neuronal development and neurodegeneration, miRNAs also play
lP

a role in brain plasticity and synapse development [83-86], which alters with any drug exposure. A study
of Chandrasekar V1 and Dreyer JL (2009) has identified a set of miRNAs (let-7d, miR-181a, and miR-
124), which plays a key role in cocaine-responsive plasticity [87]. Hollander et al., (2010), demonstrated
the role of miR-212 (striatal miRNA) in controlling cocaine intake through CREB signaling [88]. Further,
studies have also shown that methyl CpG binding protein 2 (MeCP2) is regulated by miR-212, which
na

regulates BDNF expression and cocaine intake through homeostatic interactions. Eipper-Mains JE et al.,
(2011), have identified up-regulation of the miR-8 family in cocaine-exposed striatal synapse and shown
that miR-8 regulates several synaptic proteins [89]. Zhao et al., (2013) has shown the role of miR-let-7d in
ur

TLX/microRNA-9 cascade in managing neural cell fate and neurogenesis [90]. Numerous studies are still
undergoing to find out the role of miRNAs in drug abuse and addiction, which causes neurological
disorders. There is a well-established relationship between alcohol consumption and tobacco use and, more
studies are undergoing to understand the mechanistic pathways between them. Nicotine-mediated
Jo

neurotoxicity is well established and suggested that chronic use of nicotine leads to addiction, which alters
neuronal functions and behavior. The study of Huang and Li in (2009), describes the process where nicotine
regulates Dynamin1 expression via miR-140* [91]. It has been reported by Lippi et al., in (2011) that
exposure of nicotine or cocaine up-regulates the expression of miR-29a/b in multiple brain regions as well
as in primary hippocampal neurons using mouse model [92]. Chronic use of these drugs results in unwanted
effects such as drug tolerance, opioid dependence, and addiction, and associated with structural and
functional changes in the brain. The study of Sanchez-Simon FM et al., (2010) demonstrated that morphine
regulates miR-133b: Pitx3 due to increasing Pitx3 expression in immature hippocampal neurons, therefore
promoting neurotoxicity in neuronal differentiation using zebrafish as a model [93].

Metals are another type of environmental chemicals, which have been reported to modulate the expression
of miRNAs in brain cells. Developmental exposure of heavy metals like Lead (Pb) induces epigenetic
changes in rodents, which causes alterations in the expression of several genes in adult brains [94, 95]. In
adults, chronic exposure of Pb significantly induces expression of miR-204, miR-211, miR-448, miR-449a,
and miR-34b/c, which play a crucial role in Lead- induced neurotoxicity [96]. Pb regulated miRNAs are
also reported to deregulate during neural injury, neurodegeneration, axonal, and synaptic development and
regeneration [96]. A recent study has shown that early-life exposure to Pb up-regulates expression of
Alzheimer's (AD) related miRNAs [97]. Developmental exposure of Pb modulated the expression of Tau
proteins and miR-34c in a transgenic model of Alzheimer's (AD) [98]. A study has shown that Pb induced

of
alterations in functions of the blood-brain barrier, which is mediated by miR-203, a further down-
regulatesTricellin gene [99]. Methylmercury chloride (MeHgCl) is another heavy metal, which is widely
used as a fungicide and causes adverse physiological and developmental toxicity in mammals [100, 101].

ro
MeHgCl regulated miRNAs play a role in the regulation of processes involved in axon guidance, learning
and memory, and ubiquitin-proteasome protein degradation pathway, which are the remarkable features of
neurodegenerative diseases. Studies have identified alterations in expression of various miRNAs (miR-

-p
302b, miR-367, miR-372, miR-196b, miR-141, miR-15a, miR-526b*, miR-488, miR-429, miR-146a, miR-
183, miR-339-5p, miR-9*, miR-15a*, miR-185, miR-572, miR-378*) by MeHgCl exposure in different
models [100, 101]. Copper, a metal that works as a cofactor for various proteins in several brain
re
mechanisms, while its abnormal quantity induces neuronal death. A study reported deregulation of several
miRNAs (let-7, miR-7a, miR-128, and miR-138), which takes part in neurogenesis due to Copper-mediated
toxicity using the zebrafish model [102]. Aluminum and its sulfates are also neurotoxic, which can produce
lP

Alzheimer's like symptoms in humans [103]. Exposure of Al/Fe sulfates upregulates the expression of
miRNAs (miR-9, miR-125b, and miR-128) in cultured neuronal cells as observed in Alzheimer's disease
[104]. Arsenic is another heavy metal extensively used by humans and got extensively deposited in the
environment have both neurotoxicant and carcinogenic capabilities. Arsenic is also known to cross the
blood-brain barrier and has capabilities to disrupt the neuronal structure and alters the levels of
na

neurotransmitters such as Acetylcholinesterase and Nitric oxide synthase. Few studies implicated the
associative role between arsenic and Alzheimer's [105, 106]. Arsenic exposure leads to loss of memory and
learning, which are one of the characteristic features of neurodegenerative diseases [107, 108]. Arsenic
ur

produces alterations in locomotor activity and behavior, which resembles Alzheimer's pathogenesis [109,
110]. To date, limited studies have been investigated the role of miRNAs in arsenic-induced neurotoxicity.
Arsenic is shown to regulate neural cell proliferation and apoptosis by miR-206 targeted down-regulation
of Otx2 gene [111]. More studies are needed to identify the regulation of miRNAs in different mechanisms
Jo

of arsenic neurotoxicity.

Pesticides are a major class of neurotoxicants identified for the development of neurodegenerative diseases.
The extensive use of pesticides, which are neurotoxic for humans, is considered as a major reason behind
development of different neurological disorders. Organophosphates, carbamates, pyrethroids, and
organochlorines are the major type of pesticides used for agriculture and household purpose. Most of the
organochlorine pesticides are banned years ago, but due to a very slow degradation rate, they persist in the
food chain. Cypermethrin, a class II pyrethroid, is neurotoxic for mammals due to its ability to modulate
neurotransmitters system and induce motor deficits [112]. In our recently published study, we have
demonstrated the role of miR-200 family in cypermethrin induced neuronal cell death. Exposure of
cypermethrin activates P53 proteins, which induces miR-200 and regulates levels of BCL2 protein [17].

Rotenone, Paraquat, and MPTP+ are well-known neurotoxicants, which induces PD like changes in
mammals. A recent study has shown that down-regulation of miR-384-5p protects SH-SY5Y, human
neuroblastoma cells against rotenone-induced neurotoxicity by inhibiting endoplasmic reticulum (ER)
stress regulating proteins [113]. Reporter assays have identified glucose-regulated protein 78 (GPR-78), a
master regulator of ER stress as a target of miR-384-5p [113]. Earlier studies have shown that GPR-78 is
also regulated by miR-376a in rat granulosa cells [114]. Paraquat (PQ), another pesticide that induces PD
like symptoms either in alone or combination with Maneb (fungicide) up-regulates expression of miR-195
and subsequently downregulates ADP-ribosylation factor-like protein-2 to induce apoptosis in neural
progenitor cells [115]. Our earlier studies using PC12 as a cellular model of differentiation have identified

of
miR-200 as major miRNA family up-regulated during neuronal differentiation [18]. A study that came in
2016 has shown that PQ down-regulates the expression of miR-200a, which results in the inhibition of
differentiation of neural progenitor cells due to increased levels of the beta-catenin protein [116]. Studies

ro
of Huang et al., (2014) have carried out global miRNA profiling identified miR-550 and miR-378 as major
up-regulated miRNAs in neural progenitor cells after PQ exposure [117]. An oxidative sensor protein
known as DJ-1 is down-regulated by miR-494 in MPTP induced mouse model of PD [118]. A recent study

-p
using the MPTP mouse model of PD has demonstrated the role of miR-7 in the pathogenesis of PD and
identified related inflammatory protein, i.e., Nod-like receptor protein 3 (NLRP3) as its target [119]. The
role of miR-7 mediated down-regulation of NLRP3 has also been identified in enhancing subventricular
re
zone neurogenesis in adult neural stem cells [120]. A recent study has also shown the role of miR-7 in
inhibiting neuronal apoptosis by targeting BAX and SIRT2 in a cellular model of PD [121]. Down-
regulation of BIM (a pro-apoptotic protein) by miR-124 regulates apoptosis and autophagy in the MPTP
lP

model of PD [122]. So, it has been suggested that exposure of neurotoxicants, whether metals, pesticides,
or drugs, deregulates miRNA expression, which triggers neuronal death.

Countless epidemiological and experimental studies indicated that early exposure to toxicants significantly
increased the risk of disease later in life, either during adulthood or in later ages of life. Barker (2007)
na

reported for the first time about the risk for cardiovascular diseases in context to fetal-undernutrition, which
leads to the concept of the developmental rise of diseases including neurodegenerative diseases [123] [58].
The concept of silent neurotoxicity or delayed neurotoxicity started developing approximately 30 years ago
[124]. These delays in between an exposure and clinical appearance of loss explored using two models.
ur

One model shows that toxic exposure leads to a partial loss of neuronal cells, but that is not immediate
effect as the shortage is exposed by other exogenous influences, including stress, disease, or any pharmaco-
logical substance that results in functional loss [125]. Likewise, during the aging process, the number of
Jo

living neurons got reduced, which results in a partial-functional stage due to previous toxic insults; example,
in PD and other neurodegenerative diseases, there should be an 80% loss of dopaminergic neurons to be
considered for clinical existence [126]. It is known that the aging process results in a steady loss of
dopaminergic neurons, which show around 100 years of age. But, toxicants exposure, which is responsible
for the deterioration of dopaminergic neurons, causes the overlaying aging process to result in an 80% loss
at 65 years of age with prominent signs of PD [127]. The second model suggests that toxic exposure leads
to progressive loss of neuronal cells with loss of function [124]. This loss involves epigenetic, genetic, and
biochemical effects that lead with time results in neuronal dysfunction and premature death. Several studies
have identified connecting link between early-life toxic environmental exposure and the development of
neurodegenerative diseases. Both prenatal and early postnatal exposure to neurotoxicants shown deleterious
effects on the structure and function of the nervous system. Studies identified that perinatal exposure of
metals like arsenic (As) and lead (Pb) results in age-related neurodegenerative diseases such as AD and PD
and aging like effects at later stages [128-135]. Further studies required to understand the exact molecular
mechanisms behind early exposure of neurotoxic chemicals that triggers the development of AD and PD.
However, identification of miRNAs that are known to regulate aging and neurodegeneration gives hope for
exploring the mechanism behind pathogenesis and developing therapeutics.

4. Aging-induced regulation of miRNAs

Aging is a complex biological process, which leads to time-allied deterioration of the essential life survival
physiological functions. The course of brain aging is associated with various structural, chemical, and
functional changes in the brain resulting in decreased brain mass, blood flow, neurotransmitters, synapses,

of
and cognitive abilities. Normal aging is considered without any concurrent diseases, though aged people
are more vulnerable to neurodegenerative diseases. Neurobiology studies using human brains and model

ro
organisms on brain aging have reported down-regulation of that gene, which is responsible for controlling
synaptic plasticity and mitochondrial functions [128]. Moreover, impaired protein homeostasis,
mitochondrial dysfunctions, telomeres shortening, and DNA damage are also associated with aging as well
as in age-related neurodegenerative diseases [129-134]. In the adult brain, post-mitotic cells dominate in

-p
number, which survives till the death of animals. Very few numbers of stem or progenitor cells present in
the selected part of the brain are responsible for neurogenesis capability of the adult brain. MiRNAs have
emerged as crucial regulators in several physiological processes involves the progression of normal and
re
pathological brain aging. Understanding the essential role and regulation of miRNAs and the identification
of their target genes using various models explore the molecular roots of neuronal degeneration during
aging. Studies of Zhang et al.,(2017) have shown that miRNAs residing in exosomes of hypothalamic
lP

stem/progenitor cells regulate the brain aging [135]. Their studies have observed an age-dependent decline
in the expression of exosomal miRNAs. However, treatment with the healthy hypothalamic stem or
progenitor cell-secreted exosomes slowed down the aging process, partially through the release of exosomal
miRNAs [135]. Boehm and Slack (2005) have identified miRNAs, lin-4, and its target lin-14 as a regulator
na

of larval development timing in C. elegans [136]. Later studies have shown that miRNAs can regulate the
lifespan of C. elegans both positively and negatively [136-138]. MiRNAs, which are initially discovered
for their role in regulating developmental timing and life span of C. elegans are now known as a potent
regulator of oxidative imbalance [139]. Deregulation of oxidative homeostasis is the most commonly
ur

observed mechanism in the aged brain. Studies have shown that miRNA, which regulates genes involved
in DNA damage checkpoint response pathway and the insulin signaling pathway alters longevity and aging
[137]. Studies have identified miRNAs (miR-71, miR-238, and miR-246), which independently regulate
Jo

the life span without affecting developmental processes [140, 141]. Neurodegenerative diseases, which are
usually late-onset diseases, aggravates with aging. Generalized neurodegeneration throughout the brain
with aging is an unavoidable process, but in neurodegenerative diseases like AD, PD, and HD selected part
of the brain degenerate progressively. Oxidative imbalance and proteins misfolding are two common events
in most of the neurodegenerative diseases, which indicates that the molecular mechanism of pathogenesis
and progression of these diseases could also have similarities in between and with aging. Aging affects
proteostasis of brain cells by inducing oxidative imbalance in brain cells. Three approaches are used to
manipulate the aging in experimental animals, 1) reduce the insulin signaling, 2) dietary control intake, 3)
increase mitochondrial respiration rates. Insulin/IGF-1 signaling is a major insulin pathway known to
regulate aging. Insulin/IGF-1 signaling is one of the most conserved pathways, which regulates aging and
is known to get deregulated in neurodegenerative diseases like AD, PD, and HD. Studies have shown that
the PI3K/Akt pathway is critical in the estrogen and IGF-1 neuroprotection of SNpc and dopaminergic
neurons [142]. Kim et al., (2014) have identified a miRNA (miR-126), which targets IGF-1/PI3K signaling
and contributes to PD pathogenesis [143]. Further studies of Kim et al., have shown that miR-126 acts as
an important link between metabolic dysfunction and neurotoxicity by regulating growth factor/PI3K
signaling in the aged brain and in the pathogenesis of specific neurological disorders, like PD and AD [144].
In another study, a higher expression of miR-126 was observed in the brain cells of rats, and humans also
suggested its involvement in brain functions [145]. Recently Kim et al., (2016) have shown that inhibition
of miR-126 is neuroprotective against staurosporine (non-selective inhibitor of protein kinases and
apoptosis inducer) and Aβ1-42 toxicity. Expression of miR-126 increases with aging and increases neuronal
vulnerability towards staurosporine or Alzheimer's disease (AD)-associated amyloid beta 1-42 peptides

of
(Aβ1-42). Kim et al., (2016) have shown that regulation of IGF/PI3K signaling in neurons by miR-126 acts
as an important mechanistic link between metabolic dysfunction and neurotoxicity during aging and
development of PD and AD [144]. Zhang et al.,(2015), have shown that overexpression of miR-126

ro
significantly promoted the proliferation and survival of neural stem cells [146].

Members of the miR-29 family also regulate several proteins and processes related to aging, like DNA

-p
damage, proliferation/ differentiation, and senescence. Studies have shown that P53 acts as a common link
when miR-29 is induced by aging and DNA damage in mice fibroblast [147]. Studies of Heid et al.,(2017)
have shown that the up-regulation of the miR-29 family is an endogenous mechanism of ameliorating the
re
age-dependent cardiac damage leading to hypertrophy and fibrosis [148]. Hu et al., (2014) have reported
the role of the miR-29 family in inducing cellular senescence in aging muscle [149]. Ripa et al.,(2017) show
that aging induces expression of miR-29 in the brain of short-lived turquoise killifish. Inhibiting expression
lP

of miR-29 induces a gene-expression signature typical of aging [150]. An iron delivery gene (Ireb2) is
identified as a target of miR-29 in turquoise killifish [150]. When the expression of miR-29 was inhibited
selectively in neurons, upregulation was observed in levels of IRP2 and transferrin receptor, and iron
content and oxidative stress were also increased. Takeda and Tanabe (2016) have created conditional
mutant mice, in which miR-29 was selectively knocked down in the brain through overexpression of an
na

antisense RNA transgene against miR-29 and studied the role of miR-29 family between lifespan and
reproduction [151]. Studies of Takeda and Tanabe (2016) have shown that brain-targeted miR-29
knockdown affects both lifespan and reproduction in a gender-dependent manner. Global profiling of
ur

miRNAs carried out in cortex and cerebellum of humans, chimpanzee, and Rhesus macaques have shown
consistent up-regulation in expression of miR-144 with increased age [152]. A gradual age-dependent
decrease was reported in the expression of miR-186, which targets BACE1 protein and increases the risk
of AD in aged individuals [153].
Jo

5. Similarities between aging and neurotoxicants induced neurodegeneration: Role of miRNAs

Long-lasting effects of early age neurotoxicants exposure make it difficult to differentiate the causes of
aging and neurotoxicant induced neurodegeneration. Several studies from our lab and elsewhere have
shown that exposure of neurotoxicants during prenatal or postnatal development substantially modulates
the metabolic capacity and increases the susceptibility of adults [154-156]. Aging is a complex biological
process and an essential aspect of every living individual. Long-term exposure to any harmful
environmental factors or toxicants results in deleterious or damaged cells or implicate towards senescence
or aging. Possible factors such as DNA methylation, histone modification, and noncoding RNAs have
known to contribute to the wide variety of phenotypes of aging. Among all of them, miRNAs, a class of
small noncoding RNAs, are most studied for their impact on facets of organismal aging as well as cellular
senescence. Our recent study has shown that Dicer (miRNA maturation enzyme) knockdown impairs
neuronal maturation and leads cells towards senescence, which is the hallmark of aging [157]. Studies
carried out by different groups have identified the role of miR-34, miR-29, and miR-126 families in both
neurotoxicant and aging-induced neurodegeneration. Members of the miR-34 family, which are broadly
conserved among mammals, are the best example of miRNAs connecting aging and neurotoxicants induced
neurodegeneration. Studies from our lab have shown that differentiated/mature brain cells are the richest
source of miR-34, which indicates the role of the miR-34 family in maintaining the mature neurons in the
non-proliferative stage [19, 157]. Our previous studies identified miR-34 as a brain-enriched miRNA
family, which up-regulates with neuronal maturation and brain aging, and co-operative regulation of P53

of
and miR-34a helps in neuronal differentiation by arresting cells in G1 phase [19]. Studies of Liu et
al.,(2012), using a fly model have shown that miR-34 regulates both age-associated events and long-term
brain integrity and acts as a molecular link between aging and neurodegeneration. They observed that miR-

ro
34 is brain-enriched and expressed in higher amounts at adult age in the fly. They have shown that loss of
miR-34 triggers a gene profile of accelerated brain aging, late-onset brain degeneration, and a catastrophic
decline in survival [158]. Studies have shown that miR-34 regulates PRC2 activity to release silencing of

-p
genes stimulating healthy aging [159]. Studies from our lab and elsewhere have also shown that expression
of miR-34 is regulated by P53 and in the feedback loop mechanism [19, 160, 161]. The expression of the
miR-34 family is also regulated by exposure of neurotoxicants in degenerating neurons. In PD patients,
re
downregulation of miR-34b and miR-34c correlates with decreased expression of PARK-7 and PARKIN,
two crucial proteins of PD pathogenesis [162]. Studies of Kabaria et al., (2015) have shown that
downregulation of miR-34b/c or SNP in the binding site of miR-34 at the 3'UTR of alpha-synuclein (SNCA)
lP

induces expression of SNCA, which contributes in PD pathogenesis [163]. MiR-34c is expressed

abundantly in hippocampal regions of the brain, and its expression is further upregulated by aging as well
as in Alzheimer's disease patients [164]. Isik et al.,(2016), have shown that miR-34 upregulation is
necessary for developmental arrest, correct morphogenesis, and adaptation to a lower metabolic state in C.
na

elegans to protect animals against stress-related damage [165]. Both overexpression and deletion of miR-
34 lead to an impaired stress response. They also observed a feedback loop in the regulation of miR-34.
However, it is between miR-34 and DAF-16/FOXO proteins [165]. A recent study reported the protective
role of urolithin A in preventing D-gal-induced brain aging via activating miR-34a-mediated SIRT1/mTOR
ur

signaling pathway [166]. The miR-34 family member, miR-34a has been identified to play a role in AD
pathogenesis by regulating Bcl2 expression using mouse model [167]. Till now, research is based on the
mouse model of AD, so there are some limitations, and further study is required to test the hypothesis that
Jo

altered regulation of mir-34a might be involved in the etiopathology of AD.

Studies from our lab have shown upregulation of miR-29 family during differentiation and maturation of
SH-SY5Y, human neuroblastoma [52]. Hebert et al.,(2008) have reported a relationship between loss of
miR-29a/b-1 cluster with increased BACE1 and Aβ levels in AD patients [166]. Ugalde et al.,(2011) have
identified increased expression of the miR-29 family in muscles and liver of rodents forced to accelerate
aging [147]. Ripa et al.,(2017), have shown that upregulation of miR-29 is an adaptive mechanism of brain
cells for suppressing aging activity by regulating intracellular iron homeostasis in neurons [150].
Interestingly, intracellular iron homeostasis is one of the features known to be associated with the
pathogenesis of neurological disorders [168]. Roshan et al., (2014) have shown that brain-specific
knockdown of miR-29 induces neuronal cell death and ataxia by downregulating VDAC1 protein in mice
[169]. Similarly, Papudopoloulou et al.,(2015) have also reported ataxia and cerebellar alterations in miR-
29a/b-1 knockout mice [170]. Bai et al.,(2017) have identified a decrease in the expression of miR-29 in
the serum of PD patients and suggested its use as a biomarker for PD [171]. A correlation between the
induction of miR-29 family and reduction of microglia regulatory proteins, i.e., IGF-1 and CXCL1 have
been reported by Fenn at al [172]. Pereira et al.,(2016) have demonstrated that the recombinant pre-miR-
29b decreases hBACE1 and Aβ42 levels and provides an opportunity to use it as RNA therapeutics [173].
Overall, it seems that increased miR-29 expression is required for mature and aged neurons, while down-
regulation of miR-29 family promotes neurodegenerative diseases. Studies carried out in Alzheimer's brain
expressed a downregulation of miR-107 and believed to be involved in accelerating disease progression
through regulation of BACE1 [174], which further validated in the neocortex of Alzheimer's disease brain

of
by comparing the plaques counts [175]. A follow-up study of Wang et al., (2010) identified that miR-107
has another important target progranulin which is crucial in the case of neurodegeneration[176].
Progranulin is reported to promote neural growth and regulate inflammatory responses [177]. Interestingly,

ro
progranulin deficiency is co-related with frontotemporal dementia (FTD), a first early-onset age-dependent
neurodegenerative disease. Consequently, in FTD, decreased levels of miR-107 may be beneficial to restore
progranulin levels [176]. In 2018, the collective role of miR-183/96/182 had been identified in the

-p
pathogenesis of aging and cognitive functions associated with ALS/FTD [178]. A recent study revealed
three miRNAs (miR-885-5p, miR-361-5p, and miR-17-5p) considered as possible candidates for
biomarkers in response to aging and cellular senescence with PD [179]. One of the brain-specific miRNA,
re
miR-125b, which identifies as a neuroprotector for AD [179], also participates in regulating cognitive
functions [180], which may play a biomarker role for aging and neurodegenerative diseases. Identification
of such miRNAs brings a positive direction in exploring possible triggering age-related neurodegenerative
lP

diseases.

6. Conclusion

With the breakthrough finding of miRNAs, regulation of gene expression has been explored extensively.
na

Studies carried out in past years have reported that miRNAs have a unique expression profile in the brain,
which play critical roles in neuronal development, functions, and neuronal degeneration. In addition,
recently identified brain-specific miRNAs, helped in understanding pathogenesis for brain abnormalities
associated with the aging. In recent years, several miRNAs are explored as an essential player for the
ur

aging process and its associated mechanism. In this review, we summarized studies that explored miRNAs
that participated in brain aging and neurotoxin-induced neurodegeneration. Specifically, we found studies
associated with members of miR-34, miR-29 families, and miR-126 regulates both aging and
Jo

neurotoxicants induced neurodegeneration. However, further studies will be required to fully understand
the miRNA mechanism/action in brain aging and neurodegenerative diseases to use them as a potential
therapy better. Future studies will explore the possibility that UP/Down-regulation of these miRNAs can
prevent the occurrence of neurodegenerative diseases. However, the identification of miRNAs as a
regulatory molecule of protein synthesis has opened a new window to understand the mechanism of
neurodegeneration.

7. Conflict of interest: There is no conflict of interest regarding the publication of this review article.
 8. Acknowledgments: Funding for the work in our lab has been provided by SERB, New Delhi
(GAP359). Ms. Tanisha Singh is grateful to DST, New Delhi, for providing a research fellowship.
The CSIR-IITR communication number is 3584.

9. References:

1. Vaupel, J.W., Biodemography of human ageing. Nature, 2010. 464(7288): p. 536.

2. Douglas, P.M. and A. Dillin, Protein homeostasis and aging in neurodegeneration. The Journal of
cell biology, 2010. 190(5): p. 719-729.
3. Grimm, A. and A. Eckert, Brain aging and neurodegeneration: from a mitochondrial point of view.
Journal of neurochemistry, 2017.
4. Palikaras, K. and N. Tavernarakis, Mitophagy in neurodegeneration and aging. Frontiers in

of
genetics, 2012. 3: p. 297.
5. Landrigan, P.J., et al., Early environmental origins of neurodegenerative disease in later life.
Environmental health perspectives, 2005. 113(9): p. 1230.

ro
6. Basak, I., et al., microRNAs as neuroregulators, biomarkers and therapeutic agents in
neurodegenerative diseases. Cellular and molecular life sciences, 2016. 73(4): p. 811-827.
7. Roshan, R., et al., MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug
discovery today, 2009. 14(23-24): p. 1123-1129.
8.

9.
molecular biology. 2017, Elsevier. p. 309-343.
-p
Quinlan, S., et al., MicroRNAs in neurodegenerative diseases, in International review of cell and

Di Leva, G., M. Garofalo, and C.M. Croce, MicroRNAs in cancer. Annual Review of Pathology:
re
Mechanisms of Disease, 2014. 9: p. 287-314.
10. Gommans, W.M. and E. Berezikov, Controlling miRNA regulation in disease, in Next-Generation
MicroRNA Expression Profiling Technology. 2012, Springer. p. 1-18.
lP

11. Wiemer, E.A., The role of microRNAs in cancer: no small matter. European journal of cancer, 2007.
43(10): p. 1529-1544.
12. Singh, T., et al., Regulatory triangle of neurodegeneration, adult neurogenesis and microRNAs.
2014. 13(1): p. 96-103.
13. Lai, W.-F., M. Lin, and W.-T.J.T.i.m.m. Wong, Tackling Aging by Using miRNA as a Target and a
na

Tool. 2019.
14. Fazi, F. and C. Nervi, MicroRNA: basic mechanisms and transcriptional regulatory networks for cell
fate determination. Cardiovascular research, 2008. 79(4): p. 553-561.
15. Slack, F.J., et al., The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the
ur

let-7 regulatory RNA and the LIN-29 transcription factor. Molecular cell, 2000. 5(4): p. 659-669.
16. Ambros, V., A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C.
elegans. Cell, 1989. 57(1): p. 49-57.
Jo

17. Pandey, A., et al., Transactivation of P53 by cypermethrin induced miR-200 and apoptosis in
neuronal cells. Toxicology Research, 2015. 4(6): p. 1578-1586.
18. Pandey, A., et al., Critical role of the miR‐200 family in regulating differentiation and proliferation
of neurons. Journal of neurochemistry, 2015. 133(5): p. 640-652.
19. Jauhari, A., et al., Regulation of miR-34 family in neuronal development. Molecular neurobiology,
2018. 55(2): p. 936-945.
20. Griffiths-Jones, S., et al., miRBase: tools for microRNA genomics. Nucleic acids research, 2007.
36(suppl_1): p. D154-D158.
21. Bernardo, B.C., et al., A microRNA guide for clinicians and basic scientists: background and
experimental techniques. Heart, Lung and Circulation, 2012. 21(3): p. 131-142.
22. Kakkar, P., F.N.J.E.T. Jaffery, and Pharmacology, Biological markers for metal toxicity. 2005. 19(2):
p. 335-349.
23. Swarup, D. and S. Dwivedi, Environmental pollution and effects of lead and fluoride on animal
health. 2002.
24. Cantuti-Castelvetri, I., B. Shukitt-Hale, and J.A.J.N.o.a. Joseph, Dopamine neurotoxicity: age-
dependent behavioral and histological effects. 2003. 24(5): p. 697-706.
25. Cutler, R.G., et al., Involvement of oxidative stress-induced abnormalities in ceramide and
cholesterol metabolism in brain aging and Alzheimer's disease. 2004. 101(7): p. 2070-2075.
26. Zahr, N.M., et al., Low striatal glutamate levels underlie cognitive decline in the elderly: evidence
from in vivo molecular spectroscopy. 2008. 18(10): p. 2241-2250.
27. Mochizuki, H.J.I.j.o.m.s., Arsenic Neurotoxicity in Humans. 2019. 20(14): p. 3418.
28. Halliwell, B.J.D. and aging, Role of free radicals in the neurodegenerative diseases. 2001. 18(9): p.
685-716.

of
29. Cunnane, S., et al., Brain fuel metabolism, aging, and Alzheimer’s disease. 2011. 27(1): p. 3-20.
30. Yin, F., et al., Energy metabolism and inflammation in brain aging and Alzheimer’s disease. 2016.
100: p. 108-122.

ro
31. Simpson, I.A., S.J. Vannucci, and F. Maher, Glucose transporters in mammalian brain. 1994,
Portland Press Limited.
32. Harr, S.D., et al., Functional alterations in Alzheimer's disease: decreased glucose transporter 3

-p
immunoreactivity in the perforant pathway terminal zone. 1995. 54(1): p. 38-41.
33. Reger, M., et al., Effects of intranasal insulin on cognition in memory-impaired older adults:
modulation by APOE genotype. 2006. 27(3): p. 451-458.
34. Landau, S., et al., Comparing predictors of conversion and decline in mild cognitive impairment.
re
2010. 75(3): p. 230-238.
35. Kato, T., et al., Brain fluorodeoxyglucose (FDG) PET in dementia. 2016. 30: p. 73-84.
36. Toescu, E.C., A. Verkhratsky, and P.W.J.T.i.n. Landfield, Ca2+ regulation and gene expression in
lP

normal brain aging. 2004. 27(10): p. 614-620.

37. Hu, Q. and G.J.T.n. Wang, Mitochondrial dysfunction in Parkinson’s disease. 2016. 5(1): p. 14.
38. Massano, J. and K.P.J.C.S.H.p.i.m. Bhatia, Clinical approach to Parkinson's disease: features,
diagnosis, and principles of management. 2012. 2(6): p. a008870.
39. DeBalsi, K.L., K.E. Hoff, and W.C.J.A.r.r. Copeland, Role of the mitochondrial DNA replication
na

machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. 2017. 33: p. 89-
104.
40. Chauhan, A., J. Vera, and O.J.B. Wolkenhauer, The systems biology of mitochondrial fission and
fusion and implications for disease and aging. 2014. 15(1): p. 1-12.
ur

41. Hamilton, M.L., et al., Does oxidative damage to DNA increase with age? 2001. 98(18): p. 10469-
10474.
42. Jakaria, M., et al., Neurotoxic agent-induced injury in neurodegenerative disease model: Focus on
Jo

involvement of glutamate receptors. 2018. 11: p. 307.

43. Douglas, P.M. and A.J.J.o.C.B. Dillin, Protein homeostasis and aging in neurodegeneration. 2010.
190(5): p. 719-729.
44. Brignull, H.R., J.F. Morley, and R.I. Morimoto, The Stress of Misfolded Proteins, in Molecular
aspects of the stress response: Chaperones, Membranes and Networks. 2007, Springer. p. 167-
189.
45. Kim, D.-K., et al., Mechanisms of aging-related proteinopathies in Caenorhabditis elegans. 2016.
48(10): p. e263-e263.
46. Matthews, J. and A.J.N. Scallet, Nutrition, neurotoxicants and age-related neurodegeneration.
1991. 12(3): p. 547-557.
47. Muñoz‐Manchado, A.B., et al., Chronic and progressive Parkinson's disease MPTP model in adult
and aged mice. 2016. 136(2): p. 373-387.
48. Leggio, L., et al., microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and
Therapeutic Approaches. International journal of molecular sciences, 2017. 18(12): p. 2698.
49. Koscianska, E. and W.J. Krzyzosiak, Current understanding of the role of microRNAs in
spinocerebellar ataxias. Cerebellum & ataxias, 2014. 1(1): p. 7.
50. Gao, F.-B., Posttranscriptional control of neuronal development by microRNA networks. Trends in
neurosciences, 2008. 31(1): p. 20-26.
51. Satterlee, J.S., et al., Noncoding RNAs in the brain. Journal of Neuroscience, 2007. 27(44): p.
11856-11859.
52. Jauhari, A., T. Singh, and S. Yadav, Expression of miR-145 and Its Target Proteins Are Regulated by
miR-29b in Differentiated Neurons. Molecular neurobiology, 2018: p. 1-13.
53. Yadav, S., et al., miR-497 and miR-302b regulate ethanol-induced neuronal cell death through

of
BCL2 protein and cyclin D2. Journal of Biological Chemistry, 2011. 286(43): p. 37347-37357.
54. Balaraman, S., U.H. Winzer‐Serhan, and R.C. Miranda, Opposing actions of ethanol and nicotine
on microRNAs are mediated by nicotinic acetylcholine receptors in fetal cerebral cortical–derived

ro
neural progenitor cells. Alcoholism: Clinical and Experimental Research, 2012. 36(10): p. 1669-
1677.
55. Wang, J. and Q. Cui, Specific roles of microRNAs in their interactions with environmental factors.

-p
Journal of nucleic acids, 2012. 2012.
56. Lee, D.W., et al., Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative
damage and neuronal death of ventral midbrain dopaminergic systems. Toxicological Sciences,
2011. 125(2): p. 496-508.
re
57. Peng, J., et al., Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson's
disease accelerate age-related neurodegeneration. Journal of Neuroscience, 2007. 27(26): p.
6914-6922.
lP

58. Tartaglione, A.M., A. Venerosi, and G. Calamandrei, Early-life toxic insults and onset of sporadic
neurodegenerative diseases—an overview of experimental studies, in Neurotoxin Modeling of
Brain Disorders—Life-long Outcomes in Behavioral Teratology. 2015, Springer. p. 231-264.
59. Uversky, V.N., et al., Synergistic effects of pesticides and metals on the fibrillation of α-synuclein:
implications for Parkinson’s disease. Neurotoxicology, 2002. 23(4-5): p. 527-536.
na

60. Roe, D.F., G.L. Craviso, and J.C. Waymire, Nicotinic stimulation modulates tyrosine hydroxylase
mRNA half-life and protein binding to the 3′ UTR in a manner that requires transcription. Molecular
brain research, 2004. 120(2): p. 91-102.
61. Craviso, G.L., V.B. Hemelt, and J.C. Waymire, The transient nicotinic stimulation of tyrosine
ur

hydroxylase gene transcription in bovine adrenal chromaffin cells is independent of c-fos gene
activation. Molecular brain research, 1995. 29(2): p. 233-244.
62. Bilen, J., et al., MicroRNA pathways modulate polyglutamine-induced neurodegeneration.
Jo

Molecular cell, 2006. 24(1): p. 157-163.

63. Schaefer, A., et al., Cerebellar neurodegeneration in the absence of microRNAs. Journal of
Experimental Medicine, 2007. 204(7): p. 1553-1558.
64. Sathyan, P., H.B. Golden, and R.C. Miranda, Competing interactions between micro-RNAs
determine neural progenitor survival and proliferation after ethanol exposure: evidence from an
ex vivo model of the fetal cerebral cortical neuroepithelium. Journal of Neuroscience, 2007. 27(32):
p. 8546-8557.
65. Qi, Y., et al., MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing
cerebellum through SP1/RAX/PKR cascade. Journal of Biological Chemistry, 2014. 289(14): p.
10201-10210.
66. Pietrzykowski, A.Z., et al., Posttranscriptional regulation of BK channel splice variant stability by
miR-9 underlies neuroadaptation to alcohol. Neuron, 2008. 59(2): p. 274-287.
67. Wang, L.-L., et al., Ethanol exposure induces differential microRNA and target gene expression and
teratogenic effects which can be suppressed by folic acid supplementation. Human Reproduction,
2008. 24(3): p. 562-579.
68. Tal, T.L., et al., MicroRNAs control neurobehavioral development and function in zebrafish. The
FASEB Journal, 2012. 26(4): p. 1452-1461.
69. Bahi, A. and J.L. Dreyer, Striatal modulation of BDNF expression using microRNA124a‐expressing
lentiviral vectors impairs ethanol‐induced conditioned‐place preference and voluntary alcohol
consumption. European Journal of Neuroscience, 2013. 38(2): p. 2328-2337.
70. Li, J., et al., MicroRNA expression profile and functional analysis reveal that miR‐382 is a critical
novel gene of alcohol addiction. EMBO molecular medicine, 2013. 5(9): p. 1402-1414.
71. Lippai, D., et al., Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a

of
TLR4-dependent manner in mice. PLoS One, 2013. 8(8): p. e70945.
72. Zhang, Y., et al., miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-
κB pathway. Biochemical and biophysical research communications, 2014. 452(3): p. 450-456.

ro
73. Zhang, C.R., et al., Prenatal ethanol exposure alters adult hippocampal VGLUT2 expression with
concomitant changes in promoter DNA methylation, H3K4 trimethylation and miR-467b-5p levels.
Epigenetics & chromatin, 2015. 8(1): p. 40.

-p
74. Dippold, R.P., et al., Chronic ethanol feeding alters miRNA expression dynamics during liver
regeneration. Alcoholism: Clinical and Experimental Research, 2013. 37(s1).
75. Miranda, R.C., MicroRNAs and ethanol toxicity, in International review of neurobiology. 2014,
Elsevier. p. 245-284.
re
76. Tang, Y., C.B. Forsyth, and A. Keshavarzian, The Role of miRNAs in Alcohol‐Induced Endotoxemia,
Dysfunction of Mucosal Immunity, and Gut Leakiness. Alcoholism: Clinical and Experimental
Research, 2014. 38(9): p. 2331-2334.
lP

77. Yin, H., et al., MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-
regulating SIRT1. Journal of Biological Chemistry, 2012. 287(13): p. 9817-9826.
78. Saha, B., et al., Alcohol-induced miR-27a regulates differentiation and M2 macrophage
polarization of normal human monocytes. The Journal of Immunology, 2015. 194(7): p. 3079-
3087.
na

79. Niehaus, J.L., M. Murali, and J.A. Kauer, Drugs of abuse and stress impair LTP at inhibitory synapses
in the ventral tegmental area. European journal of neuroscience, 2010. 32(1): p. 108-117.
80. Alcantara, A.A., et al., Cocaine‐and morphine‐induced synaptic plasticity in the nucleus
accumbens. Synapse, 2011. 65(4): p. 309-320.
ur

81. Graziane, N.M., et al., Opposing mechanisms mediate morphine-and cocaine-induced generation
of silent synapses. Nature neuroscience, 2016. 19(7): p. 915.
82. Nugent, F.S., E.C. Penick, and J.A. Kauer, Opioids block long-term potentiation of inhibitory
Jo

synapses. Nature, 2007. 446(7139): p. 1086.

83. Smalheiser, N.R., The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity.
Phil. Trans. R. Soc. B, 2014. 369(1652): p. 20130504.
84. Siegel, G., R. Saba, and G. Schratt, microRNAs in neurons: manifold regulatory roles at the synapse.
Current opinion in genetics & development, 2011. 21(4): p. 491-497.
85. Earls, L.R., J.J. Westmoreland, and S.S. Zakharenko, Non-coding RNA regulation of synaptic
plasticity and memory: implications for aging. Ageing research reviews, 2014. 17: p. 34-42.
86. Paschou, M., et al., miRNA regulons associated with synaptic function. PLoS One, 2012. 7(10): p.
e46189.
87. Chandrasekar, V. and J.-L. Dreyer, Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens
affects the expression, extinction, and reinstatement of cocaine-induced conditioned place
preference. Neuropsychopharmacology, 2011. 36(6): p. 1149.
88. Hollander, J.A., et al., Striatal microRNA controls cocaine intake through CREB signalling. Nature,
2010. 466(7303): p. 197.
89. Eipper-Mains, J.E., et al., microRNA-Seq reveals cocaine-regulated expression of striatal
microRNAs. RNA, 2011. 17(8): p. 1529-1543.
90. Zhao, C., et al., MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate
and neurogenesis. Scientific reports, 2013. 3: p. 1329.
91. Huang, W. and M.D. Li, Nicotine modulates expression of miR-140*, which targets the 3′-
untranslated region of dynamin 1 gene (Dnm1). International Journal of
Neuropsychopharmacology, 2009. 12(4): p. 537-546.
92. Lippi, G., et al., Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic

of
spine morphology. J Cell Biol, 2011. 194(6): p. 889-904.
93. Sanchez-Simon, F.M., et al., Morphine regulates dopaminergic neuron differentiation via miR-
133b. Molecular pharmacology, 2010. 78(5): p. 935-942.

ro
94. Eid, A., et al., Developmental lead exposure and lifespan alterations in epigenetic regulators and
their correspondence to biomarkers of Alzheimer's disease. Alzheimer's & Dementia: Diagnosis,
Assessment & Disease Monitoring, 2016. 2: p. 123-131.

-p
95. Bakheet, S.A., et al., Lead exposure: expression and activity levels of Oct-2 in the developing rat
brain. Toxicological sciences, 2006. 95(2): p. 436-442.
96. An, J., et al., The changes of miRNA expression in rat hippocampus following chronic lead exposure.
Toxicology letters, 2014. 229(1): p. 158-166.
re
97. Masoud, A.M., et al., Early-life exposure to lead (Pb) alters the expression of microRNA that target
proteins associated with Alzheimer’s disease. Journal of Alzheimer's Disease, 2016. 51(4): p. 1257-
1264.
lP

98. Dash, M., et al., Developmental exposure to lead (Pb) alters the expression of the human tau gene
and its products in a transgenic animal model. Neurotoxicology, 2016. 55: p. 154-159.
99. Su, P., et al., Mir-203-mediated tricellulin mediates lead-induced in vitro loss of blood–
cerebrospinal fluid barrier (BCB) function. Toxicology in Vitro, 2015. 29(5): p. 1185-1194.
100. Pallocca, G., et al., miRNA expression profiling in a human stem cell-based model as a tool for
na

developmental neurotoxicity testing. Cell biology and toxicology, 2013. 29(4): p. 239-257.
101. Nerini-Molteni, S., et al., MicroRNA profiling as a tool for pathway analysis in a human in vitro
model for neural development. Current medicinal chemistry, 2012. 19(36): p. 6214-6223.
102. Wang, L., et al., Copper-induced deregulation of microRNA expression in the zebrafish olfactory
ur

system. Environmental science & technology, 2013. 47(13): p. 7466-7474.

103. Yokel, R.A., The toxicology of aluminum in the brain: a review. Neurotoxicology, 2000. 21(5): p.
813-828.
Jo

104. Lukiw, W.J. and A.I. Pogue, Induction of specific micro RNA (miRNA) species by ROS-generating
metal sulfates in primary human brain cells. Journal of inorganic biochemistry, 2007. 101(9): p.
1265-1269.
105. Zarazúa, S., et al., Arsenic affects expression and processing of amyloid precursor protein (APP) in
primary neuronal cells overexpressing the Swedish mutation of human APP. International Journal
of Developmental Neuroscience, 2011. 29(4): p. 389-396.
106. Gharibzadeh, S. and S.S. Hoseini, Arsenic exposure may be a risk factor for Alzheimer’s disease.
The Journal of neuropsychiatry and clinical neurosciences, 2008. 20(4): p. 501-501.
107. Tyler, C.R. and A.M. Allan, The effects of arsenic exposure on neurological and cognitive
dysfunction in human and rodent studies: a review. Current environmental health reports, 2014.
1(2): p. 132-147.
108. BonakdarYazdi, B., et al., The effect of arsenite on spatial learning: Involvement of autophagy and
apoptosis. European journal of pharmacology, 2017. 796: p. 54-61.
109. O’Bryant, S.E., et al., Long-term low-level arsenic exposure is associated with poorer
neuropsychological functioning: a Project FRONTIER study. International journal of environmental
research and public health, 2011. 8(3): p. 861-874.
110. Gong, G. and S.E. O'Bryant, The arsenic exposure hypothesis for Alzheimer disease. Alzheimer
Disease & Associated Disorders, 2010. 24(4): p. 311-316.
111. Wang, R., et al., MiR-206 regulates neural cells proliferation and apoptosis via Otx2. Cellular
Physiology and Biochemistry, 2012. 29(3-4): p. 381-390.
112. Eells, J.T., et al., Pyrethroid insecticide-induced alterations in mammalian synaptic membrane

of
potential. Journal of Pharmacology and Experimental Therapeutics, 1992. 262(3): p. 1173-1181.
113. Jiang, M., et al., Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in
dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress. American Journal of

ro
Physiology-Cell Physiology, 2016. 310(9): p. C755-C763.
114. Iwamune, M., et al., MicroRNA-376a regulates 78-kilodalton glucose-regulated protein expression
in rat granulosa cells. PloS one, 2014. 9(10): p. e108997.

-p
115. Zhou, Y., et al., MicroRNA-195 targets ADP-ribosylation factor-like protein 2 to induce apoptosis
in human embryonic stem cell-derived neural progenitor cells. Cell death & disease, 2013. 4(6): p.
e695.
116. Huang, M., et al., Paraquat inhibited differentiation in human neural progenitor cells (hNPCs) and
re
down regulated miR-200a expression by targeting CTNNB1. Environmental toxicology and
pharmacology, 2016. 42: p. 205-211.
117. Huang, M., et al., Characterization of paraquat-induced miRNA profiling response in hNPCs
lP

undergoing proliferation. International journal of molecular sciences, 2014. 15(10): p. 18422-

18436.
118. Xiong, R., et al., MicroRNA-494 reduces DJ-1 expression and exacerbates neurodegeneration.
Neurobiology of aging, 2014. 35(3): p. 705-714.
119. Zhou, Y., et al., MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate
na

neuroinflammation in the pathogenesis of Parkinson’s disease. Molecular neurodegeneration,

2016. 11(1): p. 28.
120. Fan, Z., et al., MicroRNA-7 enhances subventricular zone neurogenesis by inhibiting
NLRP3/caspase-1 axis in adult neural stem cells. Molecular neurobiology, 2016. 53(10): p. 7057-
ur

7069.
121. Li, S., et al., MicroRNA-7 inhibits neuronal apoptosis in a cellular Parkinson’s disease model by
targeting Bax and Sirt2. American journal of translational research, 2016. 8(2): p. 993.
Jo

122. Wang, H., et al., MiR‐124 Regulates Apoptosis and Autophagy Process in MPTP Model of
Parkinson's Disease by Targeting to Bim. Brain pathology, 2016. 26(2): p. 167-176.
123. Barker, D.J.J.J.o.i.m., The origins of the developmental origins theory. 2007. 261(5): p. 412-417.
124. Reuhl, K.J.N., Delayed expression of neurotoxicity: the problem of silent damage. 1991. 12(3): p.
341-346.
125. Kraft, A.D., et al., Unmasking silent neurotoxicity following developmental exposure to
environmental toxicants. 2016. 55: p. 38-44.
126. McGeer, P., et al., Comparison of neuronal loss in Parkinson's disease and aging. 1989: p. 25-34.
127. Langston, J., et al., Predicting Parkinson's disease. Discussion. 1990. 40(10): p. 70-76.
128. Lu, T., et al., Gene regulation and DNA damage in the ageing human brain. 2004. 429(6994): p.
883.
129. López-Otín, C., et al., The hallmarks of aging. 2013. 153(6): p. 1194-1217.
130. Kourtis, N. and N.J.T.E.j. Tavernarakis, Cellular stress response pathways and ageing: intricate
molecular relationships. 2011. 30(13): p. 2520-2531.
131. Morawe, T., et al., Protein homeostasis, aging and Alzheimer’s disease. 2012. 46(1): p. 41-54.
132. Coppedè, F. and L.J.C.a.s. Migliore, DNA repair in premature aging disorders and
neurodegeneration. 2010. 3(1): p. 3-19.
133. Mecocci, P., et al., A long journey into aging, brain aging, and Alzheimer’s disease following the
oxidative stress tracks. 2018. 62(3): p. 1319-1335.
134. Grimm, A. and A.J.J.o.n. Eckert, Brain aging and neurodegeneration: from a mitochondrial point
of view. 2017. 143(4): p. 418-431.
135. Zhang, Y., et al., Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

of
2017. 548(7665): p. 52.
136. Boehm, M. and F. Slack, A developmental timing microRNA and its target regulate life span in C.
elegans. Science, 2005. 310(5756): p. 1954-1957.

ro
137. De Lencastre, A., et al., MicroRNAs both promote and antagonize longevity in C. elegans. Current
Biology, 2010. 20(24): p. 2159-2168.
138. Pincus, Z., T. Smith-Vikos, and F.J. Slack, MicroRNA predictors of longevity in Caenorhabditis

-p
elegans. PLoS genetics, 2011. 7(9): p. e1002306.
139. Ambros, V., MicroRNAs and developmental timing. Current opinion in genetics & development,
2011. 21(4): p. 511-517.
140. Abbott, A.L., Uncovering new functions for microRNAs in Caenorhabditis elegans. Current biology,
re
2011. 21(17): p. R668-R671.
141. Jin Jung, H. and Y. Suh, MicroRNA in aging: from discovery to biology. Current genomics, 2012.
13(7): p. 548-557.
lP

142. Quesada, A., B.Y. Lee, and P.E.J.D.n. Micevych, PI3 kinase/Akt activation mediates estrogen and
IGF‐1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease.
2008. 68(5): p. 632-644.
143. Kim, W., et al., miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth
factor/phosphoinositide 3-kinase signaling. Neurobiology of aging, 2014. 35(7): p. 1712-1721.
na

144. Kim, W., et al., MiR-126 regulates growth factor activities and vulnerability to toxic insult in
neurons. Molecular neurobiology, 2016. 53(1): p. 95-108.
145. Sonntag, K.C., T.-U.W. Woo, and A.M. Krichevsky, Converging miRNA functions in diverse brain
disorders: a case for miR-124 and miR-126. Experimental neurology, 2012. 235(2): p. 427-435.
ur

146. Zhang, Q., et al., Induction Function of miR-126 in Survival and Proliferation in Neural Stem Cells.
Medical science monitor: international medical journal of experimental and clinical research,
2015. 21: p. 3023.
Jo

147. Ugalde, A.P., et al., Aging and chronic DNA damage response activate a regulatory pathway
involving miR‐29 and p53. The EMBO journal, 2011. 30(11): p. 2219-2232.
148. Heid, J., et al., Age-dependent increase of oxidative stress regulates microRNA-29 family
preserving cardiac health. 2017. 7(1): p. 16839.
149. Hu, Z., et al., MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling
pathways. Aging (Albany NY), 2014. 6(3): p. 160.
150. Ripa, R., et al., MicroRNA miR-29 controls a compensatory response to limit neuronal iron
accumulation during adult life and aging. BMC biology, 2017. 15(1): p. 9.
151. Takeda, T., H.J.B. Tanabe, and b.r. communications, Lifespan and reproduction in brain-specific
miR-29-knockdown mouse. 2016. 471(4): p. 454-458.
152. Persengiev, S., et al., Genome-wide analysis of miRNA expression reveals a potential role for miR-
144 in brain aging and spinocerebellar ataxia pathogenesis. Neurobiology of aging, 2011. 32(12):
p. 2316. e17-2316. e27.
153. Kim, J., et al., miR‐186 is decreased in aged brain and suppresses BACE1 expression. Journal of
neurochemistry, 2016. 137(3): p. 436-445.
154. Slotkin, T.A. and F.J. Seidler, Developmental exposure to organophosphates triggers
transcriptional changes in genes associated with Parkinson's disease in vitro and in vivo. Brain
research bulletin, 2011. 86(5-6): p. 340-347.
155. Singh, A., et al., Imprinting of cerebral and hepatic cytochrome P450s in rat offsprings exposed
prenatally to low doses of cypermethrin. Molecular neurobiology, 2013. 48(1): p. 128-140.
156. Tolins, M., M. Ruchirawat, and P. Landrigan, The developmental neurotoxicity of arsenic: cognitive
and behavioral consequences of early life exposure. Annals of global health, 2014. 80(4): p. 303-
314.

of
157. Jauhari, A., et al., Differentiation induces dramatic changes in miRNA profile, where loss of dicer
diverts differentiating SH-SY5Y cells toward senescence. Molecular neurobiology, 2017. 54(7): p.
4986-4995.

ro
158. Liu, N., et al., The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila.
Nature, 2012. 482(7386): p. 519.
159. Kennerdell, J.R., N. Liu, and N.M.J.N.c. Bonini, MiR-34 inhibits polycomb repressive complex 2 to

-p
modulate chaperone expression and promote healthy brain aging. 2018. 9.
160. Okada, N., et al., A positive feedback between p53 and miR-34 miRNAs mediates tumor
suppression. Genes & development, 2014. 28(5): p. 438-450.
161. Lizé, M., A. Klimke, and M. Dobbelstein, MicroRNA-449 in cell fate determination. Cell cycle, 2011.
re
10(17): p. 2874-2882.
162. Miñones-Moyano, E., et al., MicroRNA profiling of Parkinson's disease brains identifies early
downregulation of miR-34b/c which modulate mitochondrial function. Human molecular genetics,
lP

2011. 20(15): p. 3067-3078.

163. Kabaria, S., et al., Inhibition of miR‐34b and miR‐34c enhances α‐synuclein expression in
Parkinson's disease. FEBS letters, 2015. 589(3): p. 319-325.
164. Zovoilis, A., et al., microRNA‐34c is a novel target to treat dementias. The EMBO journal, 2011.
30(20): p. 4299-4308.
na

165. Isik, M., T.K. Blackwell, and E.J.S.r. Berezikov, MicroRNA mir-34 provides robustness to
environmental stress response via the DAF-16 network in C. elegans. 2016. 6: p. 36766.
166. Hébert, S.S., et al., Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates
with increased BACE1/β-secretase expression. Proceedings of the National Academy of Sciences,
ur

2008. 105(17): p. 6415-6420.

167. Wang, X., et al., miR-34a, a microRNA up-regulated in a double transgenic mouse model of
Alzheimer's disease, inhibits bcl2 translation. 2009. 80(4-5): p. 268-273.
Jo

168. Double, K., et al., Impaired iron homeostasis in Parkinson’s disease, in Advances in Research on
Neurodegeneration. 2000, Springer. p. 37-58.
169. Roshan, R., et al., Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in
mice. rna, 2014. 20(8): p. 1287-1297.
170. Papadopoulou, A.S., et al., Deficiency of the miR-29a/b-1 cluster leads to ataxic features and
cerebellar alterations in mice. Neurobiology of disease, 2015. 73: p. 275-288.
171. Bai, X., et al., Downregulation of blood serum microRNA 29 family in patients with Parkinson’s
disease. Scientific Reports, 2017. 7(1): p. 5411.
172. Fenn, A.M., et al., Increased micro-RNA 29b in the aged brain correlates with the reduction of
insulin-like growth factor-1 and fractalkine ligand. Neurobiology of aging, 2013. 34(12): p. 2748-
2758.
173. Pereira, P.A., et al., Recombinant pre-miR-29b for Alzheimer s disease therapeutics. 2016. 6: p.
19946.
174. Wang, W.-X., et al., The expression of microRNA miR-107 decreases early in Alzheimer's disease
and may accelerate disease progression through regulation of β-site amyloid precursor protein-
cleaving enzyme 1. Journal of Neuroscience, 2008. 28(5): p. 1213-1223.
175. Nelson, P.T. and W.-X. Wang, MiR-107 is reduced in Alzheimer's disease brain neocortex:
validation study. Journal of Alzheimer's Disease, 2010. 21(1): p. 75-79.
176. Wang, W.-X., et al., miR-107 regulates granulin/progranulin with implications for traumatic brain
injury and neurodegenerative disease. The American journal of pathology, 2010. 177(1): p. 334-
345.

of
177. Chitramuthu, B.P., H.P. Bennett, and A.J.B. Bateman, Progranulin: a new avenue towards the
understanding and treatment of neurodegenerative disease. 2017. 140(12): p. 3081-3104.
178. Jawaid, A., et al., Memory decline and its reversal in aging and neurodegeneration involve miR-

ro
183/96/182 biogenesis. 2019. 56(5): p. 3451-3462.
179. Micheli, F., et al., Regulation of proapoptotic proteins Bak1 and p53 by miR-125b in an
experimental model of Alzheimer's disease: Protective role of 17β-estradiol. 2016. 629: p. 234-240.

-p
180. Maldonado-Lasuncion, I., et al., Aging-related changes in cognition and cortical integrity are
associated with serum expression of candidate MicroRNAs for Alzheimer disease. 2018.
re
lP
na
ur
Jo
Fig 1: Schematic representation of miRNAs as an important mechanistic link between
aging and neurotoxicity in the occurrence of neurological disorders.

of
ro
-p
re
lP
na

Fig 2: Schematic representation of pathways targeted by miRNAs deregulated in both

aging and neurotoxicity which plays a role in pathophysiology of neurological disorders.
ur
Jo
 miRNA Target Diseases Model used Reference
implicated

miR-29 Represses VDAC1, BACE-1 AD, HD, SCA Mouse [127, 130]

miR-144 Represses ATXN1 Aging, SCA1 Human, [113]

chimpanzee,
macaque

miR-34 Represses protective factors Aging, AD Fly, worm, [138, 2, 3]

Bcl2 and SIRT1 mouse

miR-126 regulating insulin/IGF- Aging, PD Rat, cells [105]

1/phosphatidylinositol-3-

of
kinase (PI3K)/AKT,
dopamine neuronal cell

ro
survival in models of
Parkinson’s disease (PD)-
associated toxicity

-p
miR-186 Suppresses BACE1 Aging/AD Mouse, Cells [114]

miR-125b Regulates Cognition related Aging/AD Mouse , Human [139, 140]

re
integrity and BAK1 and p53
proteins
lP

Table 1: MiRNAs dysregulated in Aging and Neurotoxicants induced neurodegeneration

na
ur
Jo