Next Article in Journal
microRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure
Next Article in Special Issue
MicroRNA-451 Inhibits Migration of Glioblastoma while Making It More Susceptible to Conventional Therapy
Previous Article in Journal
Evolutionary Implications of the microRNA- and piRNA Complement of Lepidodermella squamata (Gastrotricha)
Previous Article in Special Issue
Extracellular Vesicles as Conduits of Non-Coding RNA Emission and Intercellular Transfer in Brain Tumors
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
ncRNA
Volume 5
Issue 1
10.3390/ncrna5010020
ncrna-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

MicroRNA in Brain pathology: Neurodegeneration the Other Side of the Brain Cancer

by
Jakub Godlewski
1,
Jacek Lenart
2,† and
Elzbieta Salinska
2,*
1
Affiliation Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2
Affiliation Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
†
Dr. Jacek Lenart died on 18th, January, 2019.
Non-Coding RNA 2019, 5(1), 20; https://doi.org/10.3390/ncrna5010020
Submission received: 7 January 2019 / Revised: 6 February 2019 / Accepted: 15 February 2019 / Published: 23 February 2019
(This article belongs to the Special Issue Non-Coding RNA and Brain Tumors)
Browse Figure
Versions Notes

Abstract

:
The mammalian brain is made up of billions of neurons and supporting cells (glial cells), intricately connected. Molecular perturbations often lead to neurodegeneration by progressive loss of structure and malfunction of neurons, including their death. On the other side, a combination of genetic and cellular factors in glial cells, and less frequently in neurons, drive oncogenic transformation. In both situations, microenvironmental niches influence the progression of diseases and therapeutic responses. Dynamic changes that occur in cellular transcriptomes during the progression of developmental lineages and pathogenesis are controlled through a variety of regulatory networks. These include epigenetic modifications, signaling pathways, and transcriptional and post-transcriptional mechanisms. One prominent component of the latter is small non-coding RNAs, including microRNAs, that control the vast majority of these networks including genes regulating neural stemness, differentiation, apoptosis, projection fates, migration and many others. These cellular processes are also profoundly dependent on the microenvironment, stemness niche, hypoxic microenvironment, and interactions with associated cells including endothelial and immune cells. Significantly, the brain of all other mammalian organs expresses the highest number of microRNAs, with an additional gain in expression in the early stage of neurodegeneration and loss in expression in oncogenesis. However, a mechanistic explanation of the concept of an apparent inverse correlation between the odds of cancer and neurodegenerative diseases is only weakly developed. In this review, we thus will discuss widespread de-regulation of microRNAome observed in these two major groups of brain pathologies. The deciphering of these intricacies is of importance, as therapeutic restoration of pre-pathological microRNA landscape in neurodegeneration must not lead to oncogenesis and vice versa. We thus focus on microRNAs engaged in cellular processes that are inversely regulated in these diseases. We also aim to define the difference in microRNA networks between pro-survival and pro-apoptotic signaling in the brain.

1. Background

The last twenty years dramatically changed the simplified view that protein coding genes are hugged by an ocean of non-transcribed sequences. Now, the view is that protein coding genes may act largely thanks to a number of non-coding transcripts that regulate their expression, translation or activity [1]. Most of these non-coding RNAs have still unknown function. However, a small fraction of the non-coding genome gives rise to small regulatory RNAs, such as microRNAs [2], So far more than 2500 have been identified in the human genome (miRBase (www.mirbase.org)) [3] and hundreds have already been described to be functional in the brain development and pathology.
MicroRNAs are transcribed as long, single-stranded primary transcripts which form a hairpin loop structure—a signal for RNA nuclease cleavage resulting in short hairpin precursor-microRNA. Precursor-microRNAs undergo cleavage into 17–22 nucleotide-long mature microRNAs. Many microRNAs are highly conserved in other vertebrate animals. However, although they are conserved in sequence they, as other non-coding RNA, are not conserved in transcription patterns. As they regulate levels of their target messenger RNA (mRNA) through a combination of rapidly occurring mRNA destabilization and translational repression, they are potent regulators of protein expression but also other non-coding RNAs. Moreover, a single microRNA is capable of regulating hundreds of mRNA species, making them important regulators of cellular homeostasis [4]. MicroRNAs initiate the formation of inhibitory complexes by binding to partially complementary target regions within the 3′ untranslated region (3′ UTR) of specific mRNAs [5] but other mechanisms, including targeting the 5′ untranslated region (5′ UTR) or coding sequence (CDS) of the targeted mRNA, have also been reported [6,7,8,9,10,11].
Scientists have long noted an inverse correlation between the likelihood of cancer and neurodegenerative diseases. However, only scant data puts meat on the bones of that idea. Even less blended data, represent a trade-off between cancer and neurodegeneration in the context of microRNA. Inspired by a research group led by Kaleta et al. [12] who reported that the transcriptional changes seen in aging people and other vertebrates are analogous to those that occur in neurodegeneration but dissimilar from changes in cancer, we asked whether that is also true in case of microRNA. It will be essential to ensure that targeting neurodegeneration drivers or executor genes including non-coding ones do not raise cancer risk, especially in the context of a recently rapidly developing strategy of immunotherapy (as anti-inflammatory statins, for example, have been found to boost the odds of cancer) [13,14,15,16,17].

2. Neurodegeneration

The mammalian brain is a complex structure, made up of billions of neurons and glial cells, intricately connected [17]. Perturbations on synaptic connections can lead to neuronal degeneration by progressive loss of structure and malfunction of neurons, including death. The neurodegeneration is irreversible, and so far, there are no effective methods to prevent initiated processes.
Neurodegeneration is a large group of various disorders driven by a complex genetic and environmental determinant. Alzheimer’s disease (AD), Parkinson’s disease (PD) or Huntington’s disease (HD), the most often occurring neurodegenerative diseases have been the subject of investigations for many years, and many of the aspects have been disclosed [18]. Valuable information concerning the molecular mechanisms implicated in neurodegenerative diseases is related to the discovery of familial forms of these diseases, which are inherited because of specific mutations. Accumulation of aberrant or misfolded proteins, protofibril accumulation, and dysfunction of the ubiquitin-proteasome system are the commonly known landmarks of these diseases. The development of excitotoxicity, oxidative and nitrosative stress, mitochondrial injury, disturbances in synaptic transmission and inefficient axonal and dendritic transport has been reported in many slowly progressing neurodegenerative disorders [19].
Neurodegeneration can also develop after ischemic and hypoxic conditions like stroke or birth asphyxia and after accidents resulting in traumatic brain injury (TBI). Brain ischemia is a restriction in blood supply to the brain, causing not only a shortage of oxygen but also the main energy supplier—glucose. Insufficient blood supply may result from cardiac arrest (global ischemia) or can be an effect of stroke (local ischemia). In these cases, the neurodegeneration occurs for a short time in the ischemic core zone but may also slowly develop in the ischemic penumbra [20].
In the hypoxic/ischemic insults, the most critical factors are over-activation of ionotropic glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptor resulted from an increased release and extracellular retention of glutamate leads to the accumulation of toxic products (e.g., reactive oxygen species (ROS) resulting from insufficient oxygen and glucose supply) [21,22]. The shift of the cellular balance between the production and scavenging of ROS in favor of oxidants initiates oxidative stress. Cells are equipped in antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) supported by glutathione that eliminates ROS to combat oxidative stress and to neutralize reactive oxygen species; however, in ischemic conditions, these weapons usually appear insufficient.

3. Brain Cancer

Glioblastoma multiforme (GBM) has a particularly poor prognosis of only 18 months and a mean survival rate of only 3.3% at two years and 1.2% at three years [23,24,25]. This primary brain cancer is the most aggressive and lethal while being notoriously insensitive to radiation and chemotherapy. One of the reasons why GBM is so difficult to treat is the presence of extensive cellular and genetic heterogeneity, even at the single-cell level. [26,27,28]. GBM tumors are also highly invasive, infiltrating surrounding brain tissue, which makes it impossible to fully resect. Although GBM cells have distinct phenotypes, genotypes, and epigenetic landscapes, analyses on molecular diversity have focused mostly on protein-coding transcripts [28]. The global engagement and contribution of non-coding RNAs are still not sufficiently studied [29]. Recent studies showing that long-non-coding RNA [30,31] but not microRNA [32] can be used for subtype classification in GBM, underline the complexity of this cancer.

4. MicroRNA in the Brain

Multiple lines of evidence reveal several distinct mechanisms by which microRNA regulatory pathways contribute to human brain development and disease. The highly dynamic changes in microRNA expression support the emerging view that many microRNAs are expressed in cell-type-specific patterns [32,33]. Thus cell-type context may play an essential role in microRNA/mRNA targeting.
To gain insight into the function of microRNA in the pathophysiology of the brain, microRNAome profiling in neurodegeneration and oncogenesis was analyzed. This indicated apparent cell-type-specific function, as many microRNAs, including both cell/tissue-specific as well as those commonly expressed in multiple cell types, regulate the expression of cell type-specific genes. The brain, of all other mammalian organs, expresses the highest number of microRNAs [34] and therefore they have been considered as essential modulators of many brain functions in both physiological and pathological conditions. The modulatory potential of microRNAs is additionally increased by their multitargeting abilities, as one microRNA can control the expression of multiple genes.
A changed expression pattern of microRNAs has been observed in neurodegenerative disorders, ischemic brain areas and in brain tumors. The developing knowledge on the role of microRNAs in pathology and understanding of their impact on neurogenesis and neuroprotection make them a potential target for new therapeutic applications [35]. However, our understanding of the underlying cellular mechanisms of most neurological disorders is limited, as deregulated neuronal cells, likely to be the most informative, are already lost. Conversely, undifferentiated cancer stem cells are potent enough to self-renew from a single cell and therefore are an excellent source of information on disease etiology.
Therefore, pathobiology of microRNA in cancer research may allow the identification of targets for cancer and neurodegeneration leading to improved treatments for both disorders [36]. The involvement of microRNAs in the pathophysiology of neurodegeneration and brain tumors is a field of study of broad and current interest and the number of reported findings is rapidly rising and include different aspects of mentioned disorders.

5. Brain Pathology and microRNAs

Cancer and neurodegenerative diseases are influenced by common signaling pathways regulating the balance of cell survival and death [37]. Thus, the molecular machinery involved in maintaining neural function in neurodegenerative diseases may be shared with oncogenic pathways. Several microRNAs differentially expressed in neurodegenerative diseases are considered to be potential tumor suppressor microRNAs (Table 1). Indeed, cancer and neurodegenerative disorders may be influenced by common microRNA pathways that regulate differentiation, proliferation, and death of cells.

5.1. miR-9 and REST Network

Non-coding RNA transcripts are often deregulated by aberrant DNA methylation at CpG island promoters. Such a mechanism is also responsible for miR-9 (miR-9 and miR-9*) downregulation in various human cancers including brain cancers, suggesting that miR-9 is a potential tumor suppressor microRNA [38]. Indeed, miR-9 restoration in mutant EGFR driven glioma cells [39] downregulates its target FOXP1 and decrease tumorigenicity. MiR-9 is part of a feedback loop that allows tight control of the expression levels of target genes that coordinate the proliferation and migration of GBM cells [40]. In contrast to increasing colony numbers of glioblastoma stem cells via CAMTA1, miR-9 has been shown to inhibit proliferation of non-stem cell lines. Mechanistically miR-9 inhibits the proliferation and promotes the migration of glioma cells by directly targeting cyclic AMP response element-binding protein (CREB) and neurofibromin 1 (NF1), respectively [40,41,42,43]. Reduction in proliferation and tumor growth by miR-9 at the molecular level was shown to be associated with its targeting of stathmin (STMN1). On the cellular level miR-9-STMN1 targeting regulated microtubule formation during cell-cycle progression. [44]. Taking into account the complexity of the heterogeneous population of cancer cells in GBM, the majority of data still needs validation by using multiple patient-derived cells with diverse transcriptome and phenotype characteristics. The miR-9 expression is also decreased early in HD, targeting two components of the REST complex (miR-9 targets REST and miR-9* targets CoREST) [45]. MiR-9 transiently increases after brain injury and is required for axon regeneration [46]. Ectopic expression of miR-9/9∗ (but also miR-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. The miR-9-dependent repression of the EZH2-REST axis opens chromatin regions harboring REST binding sites and in consequence shapes the neuronal program [47]. MiR-9 regulates adult neurogenesis thus serving as a negative regulator providing a balance between neural stem cells (NSC) proliferation and differentiation. However, its upregulation and in consequence pro-apoptotic function was also described in PD and AD pathology. Targeting SIRT1 and BACE1 by miR-9 can affect not only on cell survival but also oxidative stress response [48,49]. The conversion of somatic cells into neurons holds great promise for regenerative medicine [50]; it is also premise in targeting cancer stem cells into the differentiative stage, and miR-9 can be one of the gatekeepers that enable deterministic reprogramming of undifferentiated cells into functional neurons [50]. The mechanisms by which miR-9/9* drive oncogenesis and neurodegeneration underline the cellular context in which these microRNAs operate [40].

5.2. miR-29 Family-Methyltransferases and Cell Death

The miR-29 family (miR-29a, miR-29b, and miR-29c) was shown to target the de novo DNA methyltransferases DNMT3A and DNMT3B. Its expression is suppressed in brain cancer cells, both differentiated and stem-like.
As a consequence of the reduced expression of the miR-29, DNMT3A and DNMT3B are overexpressed. That in turn results in aberrant DNA methylation in glioblastoma and other cancers [37,51,52,53]. MiR-29 inhibits invasion and proliferation of glioblastomas due to targeting podoplanin membrane sialoglycoprotein encoded by PDPN gene were also demonstrated [54]. Preventing de novo methylation of DNA is an important cellular anti-tumorigenic strategy. However, the described opposite result in global DNA methylation level due to overexpression of miR-29 in different cancer cell types suggested that miR-29 suppresses tumorigenesis by protecting against changes in the existing DNA methylation status [55]. Thus, the firmly established tumor suppressive function of miR-29 needs to be taken into account as the cell-specific transcriptome to understand the contrast between its anti-tumorigenic function and targeting of potent tumor suppressor PTEN [56].
There are endless discussions between cancer researchers and neuroscientists on how PTEN mutated in cancer and deregulated in neurodegeneration [57] drive opposite cellular fates. Although patients with neurodegenerative illness are generally not more susceptible to cancer, PD patients do show an increased risk for brain tumors, suggesting that context matters, and additional alterations are required for full-blown malignant transformation. A down-regulative correlation of miR-29a/b with neurodegenerative disease conditions was shown in both AD and HD [58]. Downregulation of miR-29 in AD patient samples shows an association with the upregulation of β-secretase 1 (BACE1) enzyme, which contributes to the formation of plaques by cleavage of the amyloid precursor protein (APP) [59]. Significantly, the down-regulation of miR-29 expression was also shown in the cellular model of spinocerebellar ataxia 17 (SCA17) [59]. In primary neurons and the adult mouse brain, miR-29 is highly expressed [60]; its expression is activated during cerebral and cortical maturation. The expression of miR-29 in the sympathetic nervous system inhibits apoptosis and loss of miR-29 results in neuronal cell death and ataxia implicating its function in brain pathology [58].

5.3. miR-34abc–Link to p53

One of the most broadly studied proteins in carcinogenesis, which has been recently shown to be also involved in neurodegeneration, is p53 [61,62]. MiR-34a was identified as a target of p53. It induces a cell cycle arrest, senescence, and apoptosis [63,64]. Aberrant CpG methylation of miR-34 promoter results in its loss in GBM similar to other cancers types [65,66,67,68,69]. However, its re-introduction may have a diverse effect depending on cancer driver oncogene. Indeed, overexpression of miR-34a in a subset of glioblastoma cells highly expressing PDGFRA, but not EGFR, resulting in reduced cell growth [65].
Proteins controlling the cell cycle are de-regulated in neurodegeneration. This leads to the hypothesis that, in senescent neurons, aberrations in proteins engaged in cell cycle control and apoptosis affect neuronal plasticity [65]. Terminal differentiation of neurons must be synchronized with cell cycle suppression. However, neurons can also reenter the cell cycle and undergo DNA replication [70,71,72,73].
The analysis of microRNA expression showed the downregulated profile of miR-34bc associated with pathological brain tissue in different clinical stages of PD [37,74]. Although reduction of miR-34bc expression in differentiated dopaminergic neuronal cells results in a moderate reduction in cell viability, it was accompanied by altered mitochondrial function [75]. DJ1 and Parkin were also shown to be miR-34bc indirect targets [74].
Pathogenesis of AD is also linked with the disrupted cell cycle. MiR-34a prevents cell cycle reentry and suppresses the neuronal cell cycle by targeting cyclin D1 [76]. As a consequence of miR-34a expression in cortical neurons treated with neurotoxic Aβ42 and neurons from a transgenic mouse model for AD, the aberrant increase in cyclin D1 levels occurs leading to cell cycle reentry and apoptosis of neurons. Earlier studies have shown that miR-34a is a requisite for proper neuronal differentiation, partially by targeting SIRT1 and modulating p53 activity [77,78]. p53 is known to regulate the expression of microRNAs globally either by regulating transcription of microRNAs directly or by regulating microRNA processing, and maturation machinery p53 regulate the expression of miR-34a by acting on specific binding sites on the miR-34a promoter [70]. These findings suggest that p53 may play an important role in the initiation and progression of both AD and PD via various miR-34 mediated mechanisms.

5.4. miR-124–Differentiation and Neurogenic Niche

MiR-124 is the most abundant neuronal microRNA. Biogenesis of miR-124 has discernible spatiotemporal profiles in various cells and tissues and affects a broad spectrum of biological functions in the central nervous system including its pathologies (reviewed in References [77,79]). During central nervous system development, miR-124 expression gradually increases and accumulates as neurons maturate [80,81,82]. Inhibition of miR-124 activity in selectively mature neurons leads to increased levels of non-neuronal transcripts [79,83] while increasing miR-124 activity in cancer cells showed a shift of expression profile toward that of neuronal lineage [77]. Re-introduction of miR-124 to brain cancer cells is responsible for induced morphological changes as reduced self-renewal, tumorigenicity and inhibition of invasion [84,85] by targeting SCP1, PTPN12, SNAIL2, and ROCK1, [86,87]. Such phenotype is mostly dependent on cell type, driver oncogene, and stemness status, as other report noted miR-124-dependent glioblastoma differentiation by suppressing TWIST and SNAI2 [88]. Re-expression of miR-124 in vivo increases cell death and survival of mice with intracranial xenograft tumors. MiR-124 exerts this phenotype in part by direct regulation of TEAD1, MAPK14/p38α, and SERP1 that are involved in cell proliferation and survival under stress [89].
In neurodegenerative disorders miR-124 was shown to be involved in AD, PD, and HD, as in all cases it is significantly downregulated, but in contrast to cancer cells, its low level alleviates cell death. The modulation of the subventricular zone (SVZ) neurogenic niche by miR-124 enhanced brain repair in PD model. Delivery of this microRNA is associated with the downregulation of Sox9 and Jagged1 expression, two miR-124 targets and stemness-related genes [90]. Inhibition of apoptosis in a model of PD was shown to reduce the loss of DA neurons by targeting pro-apoptotic BIM by miR-124 [91]. Widespread depression of neural genes in the caudate and motor cortex, including miR-124, is characteristic for HD. During neuronal differentiation, miR-124 plays the role of a repressor of the non-neuronal form of the splicing factor, PTB [92]. The decrease in miR-124 observed in HD may diminish the post-translational repression of non-neuronal PTB form and promote its accumulation neurons [93].
Accumulation of glutamate after ischemic stroke is closely associated with the down-regulation of expression of glutamate transporter-1 (GLT-1) – indirect miR-124 target in glial cells. In this case, neuronal miR-124 increases astroglial GLT1 expression via exosome transfer. Thus, miR-124 can be considered as a potential novel target for neuronal injuries upon cerebral ischemia [94]. Cell type-dependent targets, and in consequence phenotype driven by miR-124, provide clear evidence that supports the use of miR-124 replacement or knock-down as a new therapeutic approach to boost endogenous brain repair mechanisms in a setting of neurodegeneration while inhibiting cancer progression.

5.5. miR-128 and Neural Stem Cells Fate

MiR-128 is another microRNA abundant in healthy neurons and deregulated in both neurodegeneration and cancer [95]. Under-expression of miR-128 in brain tumor and particularly in more aggressive ones such as glioblastoma and medulloblastoma was shown in many studies [96,97,98,99,100].
The expression of miR-128 differs depending on cancer type but is consistently lost in GBM [101]. Both tumorigenicity and therapy resistance are diminished upon re-introduction of miR-128 into glioblastoma cells [100,101,102]. MiR-128 is one of the few microRNAs that shows a significant correlation with glioblastoma classification, with the most significant downregulation in mesenchymal tumors [103,104,105]. Perhaps its career in brain tumor started 10 years ago when we showed that miR-128 targeted components of Polycomb repressive complexes 1 and 2 (PRC 1/2) – BMI1 and SUZ12, respectively. Such dual targeting thereby prevented partially redundant functions of these targets [102,103,106]. As epigenetic repression of transcription driven by PRCs is linked also to tumors beyond the brain, these microRNA-mRNA targets may have broad applicability in cancer research [107,108]. Our resent study has shown that miR-128 targets also glioblastoma subtype-specific mRNAs that are relevant to the patient outcome. Such cell-specific targeting by inter-subtype transferring of microRNA by extracellular vesicle within single tumor provides a mechanistic explanation to how the gain/loss of miR-128 contributes to dynamic bidirectional transitions between the subclasses within the single tumor [103]. Glioblastoma stem cells (GSC) share characteristics with neural progenitors cells (NPCs) [109], including the expression of neural stem cell markers, the capacity for self-renewal, long-term proliferation and the formation of neurospheres. However, GSCs differ from NPC in aberrant expression of differentiation markers, chromosomal abnormalities and tumorigenicity [110,111,112,113]. MiR-128 control critical steps in committing toward neuronal lineage and maturing into terminally differentiated neurons. The importance of miR-128 in the development of the mammalian brain and their loss in tumorigenesis has been shown [102,105,114,115,116,117].
Evaluation of microRNA expression in fetal, adult and AD hippocampi showed that alteration of miR-128 contributes to neuronal dysfunction [118]. Reactive oxygen species (ROS) result in hyper-upregulation of miR-128 in cultured neurons, which suggests the possibility that microRNA may mediate ROS’s pathogenic effects in AD [119]. miR-128 is highly expressed in the hippocampus of AD patients relative to age-matched controls [120,121] and its expression is upregulated in the hippocampus in an intermediate stage of AD patients [120]. However, other studies have shown that a decrease in the miR-128 level significantly reduced apoptosis and caspase-3 activity in AD model on primary mouse cortical neurons and Neuro2a cells. In this model, Aβ mediated toxicity was decreased by targeting PPAR-γ via inactivation of NF-κB [120]. These results were confirmed in a mouse model of AD, where a miR-128 knockout weakened AD-like performances and reduced Aβ production and inflammatory responses by targeting PPARγ [122].
Multiple sclerosis (MS) is the most common immune-mediated disorder affecting the central nervous system. MiR-128 has been shown to be overexpressed in brain immune cells, serving as a pro-inflammatory microRNA. Mechanistically, these effects were mediated by direct suppression of BMI1 and interleukin-4 expression, resulting in decreased GATA3 levels, and a T-cell cytokine shift [123].
Deficiency in miR-128 leads to an increased excitability of dopamine D1 receptor-expressing neurons (D1 neurons) in the striatum and juvenile hyperactivity. It was shown that D1 neurons displaying decreased miR-128-2 show increased expression levels of ERK network regulators and increased ERK2 activation. Increased miR-128 expression reduces abnormal motor activities observed in chemically induced PD and epileptic seizures. These findings indicate miR-128-2 participation in these motor disorders [124]. Another study showed the protection of dopamine neurons from apoptosis driven by miR-128 to be associated with upregulation of the expression of excitatory amino acid transporter 4 (EAAT4) in PD. The mechanism engaged by targeting the miR-128 -AXIN1 inhibitory partner of EAAT4 [125]. MiR-128 was also shown to be decreased in the frontal cortex of transgenic HD non-human primates and correspondingly in striatum samples analyzed from both pre-symptomatic and symptomatic human patients [126]. The protective role of miR-128 against apoptosis induced by ischemia [127] together with its anti-proliferative function in cancer stem cells and pathological outcome of its hyper-expression in AD, underline not only cell type-specific function but also the importance of balanced expression. The inverse correlation of miR-128 expression levels (loss in brain malignancies, upregulation in neurodegenerative disorders) underlines the importance of balanced expression within physiological range and suggests the opposite therapeutic approaches in both cases.

5.6. miR-210 Hypoxic Signaling and Niche

Hypoxia is a perilous feature of the glioblastoma microenvironment and has been associated with poor prognosis and resistance to various therapies. Hypoxia also is associated with the downregulated profile of gene expression, so it was speculated that this is associated with widespread upregulation of microRNA. However, with few exceptions, it is not a case [128]. These include highly conserved, hypoxia-regulated microRNA - miR-210. Its expression is modulated via a hypoxia response element (HRE) within the promoter [129,130]. MiR-210 has been upregulated under hypoxic conditions in all tissues and cell types examined, and it is thus considered to be the master microRNA regulator of the hypoxia response. It is involved in numerous functions, including mitochondrial respiration, DNA repair, cell proliferation, and angiogenesis [131,132,133]. MiR-210 increases transcriptional activity of the hypoxia-inducible factor (HIF1A) and its target genes—vascular endothelial growth factor (VEGF) and carbonic anhydrase 9 (CAIX). Hypoxic survival promoted by miR-210-3p was also associated with chemo-resistance in GBM cells by targeting a negative regulator of hypoxic response, HIF3A [132]. Recently NeuroD2, the levels of which are tightly regulated by miR-210, was shown to act as a tumor suppressor and prognostic biomarker in glioblastoma [134]. As miR-210 expression is associated with hypoxia, it’s targeting of NeuroD2 links undifferentiation status of cells in a hypoxic niche with the pathogenesis of glioblastoma. However, miR-210 is detected not only in tumor cells but also in the tumor microenvironment including immune cells, highlighting the necessity of using complementary approaches to account for the cell-specific context of microRNA expression [135].
Ectopic overexpression of miR-210 has been shown to stimulate angiogenesis and proliferation of both embryonic and adult neural progenitors within the mouse brain SVZ [136,137]. It was also implicated in various models of epilepsy, as well as in vitro, in an N-methyl-D-aspartate (NMDA) receptor-dependent manner following the exposure of primary rat neurons to soluble amyloid β, a pathogenic component of AD. These results suggest a strong correlation of miR-210 regulation with neuronal activation in rodent models, as well as a likely conserved role in learning and memory in mammalian systems. Upregulation of miR-210 in a PD model reduces BDNF production and contributes to the DA neurons degeneration [138].
MiR-210 is related to vascular remodeling after ischemic injuries and its presence increases tissue perfusion and capillary density after renal ischemia/reperfusion (I/R) injury and myocardial injury [139,140,141]. Significantly higher miR-210 levels were observed in patients with good outcomes after a stroke than in those with poor outcomes. This association can be linked to the effect of miR-210 on endothelial cells. It was shown that the overexpression of miR-210 promotes the migration of endothelial cells and the formation of vascular-like structures, whereas inhibiting miR-210 expression results in a decrease of endothelial cell growth and migration, inhibition of the formation of vascular-like structures and induces apoptosis [142]. Recently, it was reported that miR-210 promotes neovascularization and neural precursor cells migration toward the infarct area after cerebral ischemia via the SOCS1-STAT3-VEGF-C pathway, facilitating nerve repair [143].
Recent data has shown that suppression of miR-210 significantly reduces the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL2 and CCL3) but did not affect anti-inflammatory factors like TGF-β or IL-10 [144].
It was shown that HI significantly increases the miR-210 level in the rat pups’ brain and that glucocorticoid receptor (GR) is a novel target of miR-210 [145,146]. MiR-210 effect of down-regulation of GR exacerbated HI evoked brain injury in rat pups. Ma and colleagues [147] also reported that increased miR-210 is involved in the disruption of the blood-brain barrier. On the other hand, Zhao [147] recently reported the down-regulated expression of miR-210 after HI connecting this with the development of HI brain edema in neonatal rats. Moreover, pre-treatment with miR-210 mimic significantly improved HI-induced edema reducing water content in brain tissue.
It was shown that intracerebroventricular or intranasal application of miR-210-LNA to silencing miR-210 resulted in a neuroprotective effect on neonatal brain HI insult [145]. The current finding that pre-treatment with miR-210 inhibitor significantly reduced HI-induced brain infarct size indicates on a functional significance of miR-210 in the pathophysiology of HI-induced brain injury in the developing brain. Moreover, miR-210 was reported to be involved in the regulation of angiogenesis in response to ischemic brain injury [148] and it was also shown that up-regulation of miR-210 protects cells from hypoxia-induced apoptosis [128]. It thus seems that the tissue type and the differences in insult character determine whether miR-210 plays a protective or detrimental.

6. More about microRNA in Neuropathology

Even though numerous microRNAs were found to be functional in neurodegenerative disorders but not in cancer, we should probably keep track of them all for the benefit of a therapeutic strategy. Deregulation of a single microRNA can drive subsequent deregulation not only of its direct targets but also indirect coding and non-coding RNAs, including other microRNAs. In addition to microRNAs reviewed in the context of neurodegeneration (miR-9, miR-21, miR-22, miR-25, miR-26, miR-29, miR-30, miR-34, miR-98, miR-106, miR-107, miR-124, miR-125, miR-127, miR-128, miR-132, miR-134, miR-141, miR-153, miR-181, miR-183, miR-186, miR-193, miR-196, miR-200, miR-210, miR-212,miR-221, miR-223, miR-320, miR-365, miR-378, miR-494, miR-505, miR-512, miR-592, miR-133b, miR-146a, miR-let7) [15,16,149,150,151] or brain cancer (miR-21, miR-17–92, Let-7, miR-10b, miR-34a, miR-7, miR-124-3p, miR-124-5p, miR-137, miR-326, miR-99a, miR-524-5p, miR-328, miR-128, miR-101, miR-302–367, miR-143, miR-145, miR-218, miR-93, miR-125b, miR-451, miR-222, miR-339, miR-148a, miR-181d, miR-297) [13,14,29,152], recently others have been identifies as potential therapeutic targets.
In case of neurodegeneration, oxidative stress dependent neurotoxicity and apoptosis was linked with following microRNAs: miR-98, miR-132, miR-153, miR-200a, miR-186, miR-221, miR-196a, miR-22, miR-107, miR-223, miR-320, miR-125b, miR-181, miR-365, miR-193, miR-49, miR-378, miR-25, miR-30d-5p, miR-26b, miR-592-5p, miR-153, miR-155, miR-212, miR-183/96/182 cluster, miR-146a [94,151,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186]. MicroRNAs that are linked to the therapy resistance and sensitivity are the ones engaged in cancer cell survival. In glioblastoma, these microRNAs are currently under investigation: miR-183/96/182, miR-143, miR-449a, miR-107, miR-122, miR-152 and miR-217 miR-200a, miR-873, let-7b, miR-136, miR-139, miR-1, miR-451, miR-143, miR-603, miR-100, miR-96, miR-93-5p, miR-146b, miR-183, miR-378, miR-125b/20b, miR-338-5b, miR-203 (Table 2) [187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204].

7. Concluding Remarks

We have discussed the importance of microRNA in brain pathologies. Changes of microRNAs profiles can serve as biomarkers of the functional status of a healthy brain, as well as of progression of CNS diseases. Interestingly, it seems that the majority of microRNAs have inverse effects in tumorigenic events and neurodegenerative processes. For example, miR-124 alleviates cell death in AD, while increases cell death in glioblastoma. This might be due to different targets involved, depending on the context of diseases and cell types. Similarly, miR-128 that is lost in glioblastoma is elevated in such neurodegenerative processes as MS or AD. Another example is miR-21 that is elevated in glioblastoma where it promotes cell growth [205], while its ectopic upregulation in undifferentiated neuroblastic cells enhances neuronal differentiation [206]. Regions of the brain with robust neurogenesis (such as SVZ and hippocampus) showed altered expression of neural fate microRNAs in both neurodegeneration and cancer [207,208]. As neural differentiation of stem and progenitor cells is associated with apoptotic cell death [209], the therapeutic use of differentiation [208] is a promising approach as we have recently shown [207]. Moreover, the regulation of numerous targets by microRNAs (summarized in Table 1) makes them good candidates for therapeutic intervention. The research on microRNA targeting is in the midst of a volte-face. Thousands of research projects have pushed ahead with the discovery of microRNA targeting for medical purposes. However, for decades we have argued that we need just a good candidate with a relevant target. Now we think that this is less about small RNA reintroduction that has been overstated but more about the rigorous studies of microRNA in relevant models. Currently, only a few microRNAs, such as miR-128, are poised to replace single gene therapies for the treatment of these brain diseases shortly (Figure 1).

Author Contributions

Conceptualization, literature search, discussion and writing J.L., J.G., E.S.

Funding

This project was supported by a National Institute of Health (NCI 1R01 CA176203-01A1, to J.G) and National Science Centre Poland (NCN 2014/15/B/NZ4/04487).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ulitsky, I.; Bartel, D.P. lincRNAs: Genomics, evolution, and mechanisms. Cell 2013, 154, 26–46. [Google Scholar] [CrossRef] [PubMed]
  2. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854. [Google Scholar] [CrossRef]
  3. Kozomara, A.; Griffiths-Jones, S. miRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014, 42, D68–D73. [Google Scholar] [CrossRef] [PubMed]
  4. Eichhorn, C.D.; Kang, M.; Feigon, J. Structure and function of preQ1 riboswitches. Biochim. Et Biophys. Acta 2014, 1839, 939–950. [Google Scholar] [CrossRef] [PubMed]
  5. Carthew, R.W.; Sontheimer, E.J. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009, 136, 642–655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Miranda, K.C.; Huynh, T.; Tay, Y.; Ang, Y.S.; Tam, W.L.; Thomson, A.M.; Lim, B.; Rigoutsos, I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell 2006, 126, 1203–1217. [Google Scholar] [CrossRef] [PubMed]
  7. Lee, I.; Ajay, S.S.; Yook, J.I.; Kim, H.S.; Hong, S.H.; Kim, N.H.; Dhanasekaran, S.M.; Chinnaiyan, A.M.; Athey, B.D. New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res. 2009, 19, 1175–1183. [Google Scholar] [CrossRef] [PubMed]
  8. Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Gaudio, E.; Santhanam, R.; Lovat, F.; Fadda, P.; Mao, C.; Nuovo, G.J.; et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA 2012, 109, E2110–E2116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Vasudevan, S.; Tong, Y.; Steitz, J.A. Switching from repression to activation: microRNAs can up-regulate translation. Science 2007, 318, 1931–1934. [Google Scholar] [CrossRef] [PubMed]
  10. Eiring, A.M.; Harb, J.G.; Neviani, P.; Garton, C.; Oaks, J.J.; Spizzo, R.; Liu, S.; Schwind, S.; Santhanam, R.; Hickey, C.J.; et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 2010, 140, 652–665. [Google Scholar] [CrossRef] [PubMed]
  11. Orom, U.A.; Nielsen, F.C.; Lund, A.H. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 2008, 30, 460–471. [Google Scholar] [CrossRef] [PubMed]
  12. Aramillo Irizar, P.; Schauble, S.; Esser, D.; Groth, M.; Frahm, C.; Priebe, S.; Baumgart, M.; Hartmann, N.; Marthandan, S.; Menzel, U.; et al. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. Nat. Commun. 2018, 9, 327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Godlewski, J.; Krichevsky, A.M.; Johnson, M.D.; Chiocca, E.A.; Bronisz, A. Belonging to a network--microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Neuro-Oncol. 2015, 17, 652–662. [Google Scholar] [CrossRef] [PubMed]
  14. Floyd, D.; Purow, B. Micro-masters of glioblastoma biology and therapy: Increasingly recognized roles for microRNAs. Neuro-Oncol. 2014, 16, 622–627. [Google Scholar] [CrossRef] [PubMed]
  15. Quinlan, S.; Kenny, A.; Medina, M.; Engel, T.; Jimenez-Mateos, E.M. MicroRNAs in Neurodegenerative Diseases. Int. Rev. Cell Mol. Biol. 2017, 334, 309–343. [Google Scholar] [PubMed]
  16. Ferrante, M.; Conti, G.O. Environment and Neurodegenerative Diseases: An Update on miRNA Role. MicroRNA 2017, 6, 157–165. [Google Scholar] [CrossRef] [PubMed]
  17. Rajgor, D.; Hanley, J.G. The Ins and Outs of miRNA-Mediated Gene Silencing during Neuronal Synaptic Plasticity. Non-Coding Rna 2016, 2, 1. [Google Scholar] [CrossRef] [PubMed]
  18. Bossy-Wetzel, E.; Schwarzenbacher, R.; Lipton, S.A. Molecular pathways to neurodegeneration. Nat. Med. 2004, 10, S2–S9. [Google Scholar] [CrossRef] [PubMed]
  19. Jellinger, K.A. Basic mechanisms of neurodegeneration: A critical update. J. Cell. Mol. Med. 2010, 14, 457–487. [Google Scholar] [CrossRef] [PubMed]
  20. Radak, D.; Katsiki, N.; Resanovic, I.; Jovanovic, A.; Sudar-Milovanovic, E.; Zafirovic, S.; A Mousad, S.; R Isenovic, E. Apoptosis and acute brain ischemia in ischemic stroke. Curr. Vasc. Pharmacol. 2017, 15, 115–122. [Google Scholar] [CrossRef] [PubMed]
  21. Bratek, E.; Ziembowicz, A.; Bronisz, A.; Salinska, E. The activation of group II metabotropic glutamate receptors protects neonatal rat brains from oxidative stress injury after hypoxia-ischemia. PLoS ONE 2018, 13, e0200933. [Google Scholar] [CrossRef] [PubMed]
  22. Chen, H.; Yoshioka, H.; Kim, G.S.; Jung, J.E.; Okami, N.; Sakata, H.; Maier, C.M.; Narasimhan, P.; Goeders, C.E.; Chan, P.H. Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid. Redox Signal. 2011, 14, 1505–1517. [Google Scholar] [CrossRef] [PubMed]
  23. Furnari, F.B.; Fenton, T.; Bachoo, R.M.; Mukasa, A.; Stommel, J.M.; Stegh, A.; Hahn, W.C.; Ligon, K.L.; Louis, D.N.; Brennan, C.; et al. Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 2007, 21, 2683–2710. [Google Scholar] [CrossRef] [PubMed]
  24. Ohgaki, H.; Dessen, P.; Jourde, B.; Horstmann, S.; Nishikawa, T.; Di Patre, P.L.; Burkhard, C.; Schuler, D.; Probst-Hensch, N.M.; Maiorka, P.C.; et al. Genetic pathways to glioblastoma: A population-based study. Cancer Res. 2004, 64, 6892–6899. [Google Scholar] [CrossRef] [PubMed]
  25. Ohgaki, H.; Kleihues, P. Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 2007, 170, 1445–1453. [Google Scholar] [CrossRef] [PubMed]
  26. Meyer, M.; Reimand, J.; Lan, X.; Head, R.; Zhu, X.; Kushida, M.; Bayani, J.; Pressey, J.C.; Lionel, A.C.; Clarke, I.D.; et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc. Natl. Acad. Sci. USA 2015, 112, 851–856. [Google Scholar] [CrossRef] [PubMed]
  27. Friedmann-Morvinski, D. Glioblastoma heterogeneity and cancer cell plasticity. Crit. Rev. Oncog. 2014, 19, 327–336. [Google Scholar] [CrossRef] [PubMed]
  28. Patel, A.P.; Tirosh, I.; Trombetta, J.J.; Shalek, A.K.; Gillespie, S.M.; Wakimoto, H.; Cahill, D.P.; Nahed, B.V.; Curry, W.T.; Martuza, R.L.; et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014, 344, 1396–1401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Bronisz, A.; Godlewski, J.; Chiocca, E.A. Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors. Cell. Mol. Neurobiol. 2016, 36, 361–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Du, Z.; Fei, T.; Verhaak, R.G.; Su, Z.; Zhang, Y.; Brown, M.; Chen, Y.; Liu, X.S. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat. Struct. Mol. Biol. 2013, 20, 908–913. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Mineo, M.; Ricklefs, F.; Rooj, A.K.; Lyons, S.M.; Ivanov, P.; Ansari, K.I.; Nakano, I.; Chiocca, E.A.; Godlewski, J.; Bronisz, A. The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches. Cell Rep. 2016, 15, 2500–2509. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Godlewski, J.; Ferrer-Luna, R.; Rooj, A.K.; Mineo, M.; Ricklefs, F.; Takeda, Y.S.; Nowicki, M.O.; Salinska, E.; Nakano, I.; Lee, H.; et al. MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer. Stem Cell Rep. 2017, 8, 1497–1505. [Google Scholar] [CrossRef] [PubMed]
  33. Li, X.; Yang, L.; Chen, L.L. The Biogenesis, Functions, and Challenges of Circular RNAs. Mol. Cell 2018, 71, 428–442. [Google Scholar] [CrossRef] [PubMed]
  34. Sempere, L.F.; Freemantle, S.; Pitha-Rowe, I.; Moss, E.; Dmitrovsky, E.; Ambros, V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 2004, 5, R13. [Google Scholar] [CrossRef] [PubMed]
  35. Plun-Favreau, H.; Lewis, P.A.; Hardy, J.; Martins, L.M.; Wood, N.W. Cancer and neurodegeneration: Between the devil and the deep blue sea. Plos Genet. 2010, 6, e1001257. [Google Scholar] [CrossRef] [PubMed]
  36. Saugstad, J.A. MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J. Cereb. Blood Flow Metab. 2010, 30, 1564–1576. [Google Scholar] [CrossRef] [PubMed]
  37. Saito, Y.; Saito, H. MicroRNAs in cancers and neurodegenerative disorders. Front. Genet. 2012, 3, 194. [Google Scholar] [CrossRef] [PubMed]
  38. Yuan, G.Q.; Wei, N.L.; Mu, L.Y.; Wang, X.Q.; Zhang, Y.N.; Zhou, W.N.; Pan, Y.W. A 4-miRNAs signature predicts survival in glioblastoma multiforme patients. Cancer Biomark. Sect. A Dis. Markers 2017, 20, 443–452. [Google Scholar] [CrossRef] [PubMed]
  39. Gomez, G.G.; Volinia, S.; Croce, C.M.; Zanca, C.; Li, M.; Emnett, R.; Gutmann, D.H.; Brennan, C.W.; Furnari, F.B.; Cavenee, W.K. Suppression of microRNA-9 by mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity. Cancer Res. 2014, 74, 1429–1439. [Google Scholar] [CrossRef] [PubMed]
  40. Nowek, K.; Wiemer, E.A.C.; Jongen-Lavrencic, M. The versatile nature of miR-9/9(*) in human cancer. Oncotarget 2018, 9, 20838–20854. [Google Scholar] [CrossRef] [PubMed]
  41. Schraivogel, D.; Weinmann, L.; Beier, D.; Tabatabai, G.; Eichner, A.; Zhu, J.Y.; Anton, M.; Sixt, M.; Weller, M.; Beier, C.P.; et al. CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J. 2011, 30, 4309–4322. [Google Scholar] [CrossRef] [PubMed]
  42. Carro, M.S.; Lim, W.K.; Alvarez, M.J.; Bollo, R.J.; Zhao, X.; Snyder, E.Y.; Sulman, E.P.; Anne, S.L.; Doetsch, F.; Colman, H.; et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010, 463, 318–325. [Google Scholar] [CrossRef] [PubMed]
  43. Tan, X.; Wang, S.; Yang, B.; Zhu, L.; Yin, B.; Chao, T.; Zhao, J.; Yuan, J.; Qiang, B.; Peng, X. The CREB-miR-9 negative feedback minicircuitry coordinates the migration and proliferation of glioma cells. PLoS ONE 2012, 7, e49570. [Google Scholar] [CrossRef] [PubMed]
  44. Song, Y.; Mu, L.; Han, X.; Li, Q.; Dong, B.; Li, H.; Liu, X. MicroRNA-9 inhibits vasculogenic mimicry of glioma cell lines by suppressing Stathmin expression. J. Neuro-Oncol. 2013, 115, 381–390. [Google Scholar] [CrossRef] [PubMed]
  45. Packer, A.N.; Xing, Y.; Harper, S.Q.; Jones, L.; Davidson, B.L. The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J. Neurosci. Off. J. Soc. Neurosci. 2008, 28, 14341–14346. [Google Scholar] [CrossRef] [PubMed]
  46. Oh, Y.M.; Mahar, M.; Ewan, E.E.; Leahy, K.M.; Zhao, G.; Cavalli, V. Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration. Proc. Natl. Acad. Sci. USA 2018, 115. [Google Scholar] [CrossRef] [PubMed]
  47. Lee, S.W.; Oh, Y.M.; Lu, Y.L.; Kim, W.K.; Yoo, A.S. MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts. Dev. Cell 2018, 46, 73–84. [Google Scholar] [CrossRef] [PubMed]
  48. Rostamian Delavar, M.; Baghi, M.; Safaeinejad, Z.; Kiani-Esfahani, A.; Ghaedi, K.; Nasr-Esfahani, M.H. Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease. Gene 2018, 662, 54–65. [Google Scholar] [CrossRef] [PubMed]
  49. Schonrock, N.; Humphreys, D.T.; Preiss, T.; Gotz, J. Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-beta. J. Mol. Neurosci. Mn 2012, 46, 324–335. [Google Scholar] [CrossRef] [PubMed]
  50. Xue, Y.; Qian, H.; Hu, J.; Zhou, B.; Zhou, Y.; Hu, X.; Karakhanyan, A.; Pang, Z.; Fu, X.D. Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells. Nat. Neurosci. 2016, 19, 807–815. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Ru, P.; Hu, P.; Geng, F.; Mo, X.; Cheng, C.; Yoo, J.Y.; Cheng, X.; Wu, X.; Guo, J.Y.; Nakano, I.; et al. Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth. Cell Rep. 2017, 18, 1076–1077. [Google Scholar] [CrossRef] [PubMed]
  52. Xu, H.; Sun, J.; Shi, C.; Sun, C.; Yu, L.; Wen, Y.; Zhao, S.; Liu, J.; Xu, J.; Li, H.; et al. miR-29s inhibit the malignant behavior of U87MG glioblastoma cell line by targeting DNMT3A and 3B. Neurosci. Lett. 2015, 590, 40–46. [Google Scholar] [CrossRef] [PubMed]
  53. Fabbri, M.; Garzon, R.; Cimmino, A.; Liu, Z.; Zanesi, N.; Callegari, E.; Liu, S.; Alder, H.; Costinean, S.; Fernandez-Cymering, C.; et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc. Natl. Acad. Sci. USA 2007, 104, 15805–15810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Cortez, M.A.; Nicoloso, M.S.; Shimizu, M.; Rossi, S.; Gopisetty, G.; Molina, J.R.; Carlotti, C., Jr.; Tirapelli, D.; Neder, L.; Brassesco, M.S.; et al. miR-29b and miR-125a regulate podoplanin and suppress invasion in glioblastoma. GenesChromosomes Cancer 2010, 49, 981–990. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Morita, S.; Horii, T.; Kimura, M.; Ochiya, T.; Tajima, S.; Hatada, I. miR-29 represses the activities of DNA methyltransferases and DNA demethylases. Int. J. Mol. Sci. 2013, 14, 14647–14658. [Google Scholar] [CrossRef] [PubMed]
  56. Tumaneng, K.; Schlegelmilch, K.; Russell, R.C.; Yimlamai, D.; Basnet, H.; Mahadevan, N.; Fitamant, J.; Bardeesy, N.; Camargo, F.D.; Guan, K.L. YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nat. Cell Biol. 2012, 14, 1322–1329. [Google Scholar] [CrossRef] [PubMed]
  57. Ihle, N.T.; Abraham, R.T. The Pten-Parkin Axis: At the Nexus of Cancer and Neurodegeneration. Mol. Cell 2017, 65, 959–960. [Google Scholar] [CrossRef] [PubMed]
  58. Roshan, R.; Shridhar, S.; Sarangdhar, M.A.; Banik, A.; Chawla, M.; Garg, M.; Singh, V.P.; Pillai, B. Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA 2014, 20, 1287–1297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Hebert, S.S.; Horre, K.; Nicolai, L.; Papadopoulou, A.S.; Mandemakers, W.; Silahtaroglu, A.N.; Kauppinen, S.; Delacourte, A.; De Strooper, B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc. Natl. Acad. Sci. USA 2008, 105, 6415–6420. [Google Scholar] [CrossRef] [PubMed]
  60. Jovicic, A.; Roshan, R.; Moisoi, N.; Pradervand, S.; Moser, R.; Pillai, B.; Luthi-Carter, R. Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J. Neurosci. Off. J. Soc. Neurosci. 2013, 33, 5127–5137. [Google Scholar] [CrossRef] [PubMed]
  61. Zilfou, J.T.; Lowe, S.W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 2009, 1, a001883. [Google Scholar] [CrossRef] [PubMed]
  62. Godar, S.; Ince, T.A.; Bell, G.W.; Feldser, D.; Donaher, J.L.; Bergh, J.; Liu, A.; Miu, K.; Watnick, R.S.; Reinhardt, F.; et al. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 2008, 134, 62–73. [Google Scholar] [CrossRef] [PubMed]
  63. He, L.; Hannon, G.J. MicroRNAs: Small RNAs with a big role in gene regulation. Nat. Rev. Genet. 2004, 5, 522–531. [Google Scholar] [CrossRef] [PubMed]
  64. Tazawa, H.; Tsuchiya, N.; Izumiya, M.; Nakagama, H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl. Acad. Sci. USA 2007, 104, 15472–15477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Silber, J.; Jacobsen, A.; Ozawa, T.; Harinath, G.; Pedraza, A.; Sander, C.; Holland, E.C.; Huse, J.T. miR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and promotes tumorigenesis. PLoS ONE 2012, 7, e33844. [Google Scholar] [CrossRef] [PubMed]
  66. Okada, N.; Lin, C.P.; Ribeiro, M.C.; Biton, A.; Lai, G.; He, X.; Bu, P.; Vogel, H.; Jablons, D.M.; Keller, A.C.; et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev. 2014, 28, 438–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Pichiorri, F.; Suh, S.S.; Rocci, A.; De Luca, L.; Taccioli, C.; Santhanam, R.; Zhou, W.; Benson, D.M., Jr.; Hofmainster, C.; Alder, H.; et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development. Cancer Cell 2016, 30, 349–351. [Google Scholar] [CrossRef] [PubMed]
  68. Fabbri, M.; Bottoni, A.; Shimizu, M.; Spizzo, R.; Nicoloso, M.S.; Rossi, S.; Barbarotto, E.; Cimmino, A.; Adair, B.; Wojcik, S.E.; et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 2011, 305, 59–67. [Google Scholar] [CrossRef] [PubMed]
  69. Lodygin, D.; Tarasov, V.; Epanchintsev, A.; Berking, C.; Knyazeva, T.; Korner, H.; Knyazev, P.; Diebold, J.; Hermeking, H. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008, 7, 2591–2600. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Jauhari, A.; Singh, T.; Singh, P.; Parmar, D.; Yadav, S. Regulation of miR-34 Family in Neuronal Development. Mol. Neurobiol. 2018, 55, 936–945. [Google Scholar] [CrossRef] [PubMed]
  71. Herrup, K.; Yang, Y. Cell cycle regulation in the postmitotic neuron: Oxymoron or new biology? Nat. Rev. Neurosci. 2007, 8, 368–378. [Google Scholar] [CrossRef] [PubMed]
  72. Park, D.S.; Morris, E.J.; Stefanis, L.; Troy, C.M.; Shelanski, M.L.; Geller, H.M.; Greene, L.A. Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress. J. Neurosci. Off. J. Soc. Neurosci. 1998, 18, 830–840. [Google Scholar] [CrossRef]
  73. Craven, D.E.; Regan, A.M. Nosocomial pneumonia in the ICU patient. Crit. Care Nurs. Q. 1989, 11, 28–44. [Google Scholar] [CrossRef] [PubMed]
  74. Minones-Moyano, E.; Porta, S.; Escaramis, G.; Rabionet, R.; Iraola, S.; Kagerbauer, B.; Espinosa-Parrilla, Y.; Ferrer, I.; Estivill, X.; Marti, E. MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum. Mol. Genet. 2011, 20, 3067–3078. [Google Scholar] [CrossRef] [PubMed]
  75. Shanesazzade, Z.; Peymani, M.; Ghaedi, K.; Nasr Esfahani, M.H. miR-34a/BCL-2 signaling axis contributes to apoptosis in MPP(+) -induced SH-SY5Y cells. Mol. Genet. Genom. Med. 2018, 6. [Google Scholar] [CrossRef] [PubMed]
  76. Modi, P.K.; Jaiswal, S.; Sharma, P. Regulation of Neuronal Cell Cycle and Apoptosis by MicroRNA 34a. Mol. Cell. Biol. 2016, 36, 84–94. [Google Scholar] [PubMed]
  77. Navarro, F.; Lieberman, J. miR-34 and p53: New Insights into a Complex Functional Relationship. PLoS ONE 2015, 10, e0132767. [Google Scholar] [CrossRef] [PubMed]
  78. Aranha, M.M.; Santos, D.M.; Sola, S.; Steer, C.J.; Rodrigues, C.M. miR-34a regulates mouse neural stem cell differentiation. PLoS ONE 2011, 6, e21396. [Google Scholar] [CrossRef] [PubMed]
  79. Sun, Y.; Luo, Z.M.; Guo, X.M.; Su, D.F.; Liu, X. An updated role of microRNA-124 in central nervous system disorders: A review. Front. Cell. Neurosci. 2015, 9, 193. [Google Scholar] [CrossRef] [PubMed]
  80. Deo, M.; Yu, J.Y.; Chung, K.H.; Tippens, M.; Turner, D.L. Detection of mammalian microRNA expression by in situ hybridization with RNA oligonucleotides. Dev. Dyn. 2006, 235, 2538–2548. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Krichevsky, A.M.; Sonntag, K.C.; Isacson, O.; Kosik, K.S. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006, 24, 857–864. [Google Scholar] [CrossRef] [PubMed]
  82. Smirnova, L.; Grafe, A.; Seiler, A.; Schumacher, S.; Nitsch, R.; Wulczyn, F.G. Regulation of miRNA expression during neural cell specification. Eur. J. Neurosci. 2005, 21, 1469–1477. [Google Scholar] [CrossRef] [PubMed]
  83. Conaco, C.; Otto, S.; Han, J.J.; Mandel, G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc. Natl. Acad. Sci. USA 2006, 103, 2422–2427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Silber, J.; Lim, D.A.; Petritsch, C.; Persson, A.I.; Maunakea, A.K.; Yu, M.; Vandenberg, S.R.; Ginzinger, D.G.; James, C.D.; Costello, J.F.; et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6, 14. [Google Scholar] [CrossRef] [PubMed]
  85. Fowler, A.; Thomson, D.; Giles, K.; Maleki, S.; Mreich, E.; Wheeler, H.; Leedman, P.; Biggs, M.; Cook, R.; Little, N.; et al. miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion. Eur. J. Cancer 2011, 47, 953–963. [Google Scholar] [CrossRef] [PubMed]
  86. Conti, L.; Crisafulli, L.; Caldera, V.; Tortoreto, M.; Brilli, E.; Conforti, P.; Zunino, F.; Magrassi, L.; Schiffer, D.; Cattaneo, E. REST controls self-renewal and tumorigenic competence of human glioblastoma cells. PLoS ONE 2012, 7, e38486. [Google Scholar] [CrossRef] [PubMed]
  87. An, L.; Liu, Y.; Wu, A.; Guan, Y. microRNA-124 inhibits migration and invasion by down-regulating ROCK1 in glioma. PLoS ONE 2013, 8, e69478. [Google Scholar] [CrossRef] [PubMed]
  88. Xie, Y.K.; Huo, S.F.; Zhang, G.; Zhang, F.; Lian, Z.P.; Tang, X.L.; Jin, C. CDA-2 induces cell differentiation through suppressing Twist/SLUG signaling via miR-124 in glioma. J. Neuro-Oncol. 2012, 110, 179–186. [Google Scholar] [CrossRef] [PubMed]
  89. Mucaj, V.; Lee, S.S.; Skuli, N.; Giannoukos, D.N.; Qiu, B.; Eisinger-Mathason, T.S.; Nakazawa, M.S.; Shay, J.E.; Gopal, P.P.; Venneti, S.; et al. MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 2015, 34, 2204–2214. [Google Scholar] [CrossRef] [PubMed]
  90. Saraiva, C.; Paiva, J.; Santos, T.; Ferreira, L.; Bernardino, L. MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson’s disease. J. Control. Release 2016, 235, 291–305. [Google Scholar] [CrossRef] [PubMed]
  91. Wang, H.; Ye, Y.; Zhu, Z.; Mo, L.; Lin, C.; Wang, Q.; Wang, H.; Gong, X.; He, X.; Lu, G.; et al. MiR-124 regulates apoptosis and autophagy process in mptp model of Parkinson’s disease by targeting to bim. Brain Pathol. 2016, 26, 167–176. [Google Scholar] [CrossRef] [PubMed]
  92. Makeyev, E.V.; Zhang, J.; Carrasco, M.A.; Maniatis, T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 2007, 27, 435–448. [Google Scholar] [CrossRef] [PubMed]
  93. Johnson, R.; Buckley, N.J. Gene dysregulation in Huntington’s disease: REST, microRNAs and beyond. Neuromolecular Med. 2009, 11, 183–199. [Google Scholar] [CrossRef] [PubMed]
  94. Majdi, A.; Mahmoudi, J.; Sadigh-Eteghad, S.; Farhoudi, M.; Shotorbani, S.S. The interplay of microRNAs and post-ischemic glutamate excitotoxicity: An emergent research field in stroke medicine. Neurol. Sci. 2016, 37, 1765–1771. [Google Scholar] [CrossRef] [PubMed]
  95. Campbell, K.; Booth, S.A. MicroRNA in neurodegenerative drug discovery: The way forward? Expert Opin. Drug Discov. 2015, 10, 9–16. [Google Scholar] [CrossRef] [PubMed]
  96. Ciafre, S.A.; Galardi, S.; Mangiola, A.; Ferracin, M.; Liu, C.G.; Sabatino, G.; Negrini, M.; Maira, G.; Croce, C.M.; Farace, M.G. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem. Biophys. Res. Commun. 2005, 334, 1351–1358. [Google Scholar] [CrossRef] [PubMed]
  97. Lo, U.G.; Pong, R.C.; Yang, D.; Gandee, L.; Hernandez, E.; Dang, A.; Lin, C.J.; Santoyo, J.; Ma, S.; Sonavane, R.; et al. IFN-r-induced IFIT5 promotes epithelial-to-mesenchymal transition in prostate cancer via microRNA processing. Cancer Res. 2018. [Google Scholar] [CrossRef] [PubMed]
  98. He, F.; Song, Z.; Chen, H.; Chen, Z.; Yang, P.; Li, W.; Yang, Z.; Zhang, T.; Wang, F.; Wei, J.; et al. Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene 2018, 38. [Google Scholar] [CrossRef] [PubMed]
  99. Li, M.; Fu, W.; Wo, L.; Shu, X.; Liu, F.; Li, C. miR-128 and its target genes in tumorigenesis and metastasis. Exp. Cell Res. 2013, 319, 3059–3064. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Zhu, Y.; Yu, F.; Jiao, Y.; Feng, J.; Tang, W.; Yao, H.; Gong, C.; Chen, J.; Su, F.; Zhang, Y.; et al. Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin. Cancer Res. 2011, 17, 7105–7115. [Google Scholar] [CrossRef] [PubMed]
  101. Volinia, S.; Calin, G.A.; Liu, C.G.; Ambs, S.; Cimmino, A.; Petrocca, F.; Visone, R.; Iorio, M.; Roldo, C.; Ferracin, M.; et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA 2006, 103, 2257–2261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Peruzzi, P.; Bronisz, A.; Nowicki, M.O.; Wang, Y.; Ogawa, D.; Price, R.; Nakano, I.; Kwon, C.H.; Hayes, J.; Lawler, S.E.; et al. MicroRNA-128 coordinately targets polycomb repressor complexes in glioma stem cells. Neuro-Oncol. 2013, 15, 1212–1224. [Google Scholar] [CrossRef] [PubMed]
  103. Rooj, A.K.; Ricklefs, F.; Mineo, M.; Nakano, I.; Chiocca, E.A.; Bronisz, A.; Godlewski, J. MicroRNA-mediated dynamic bidirectional shift between the subclasses of glioblastoma stem-like cells. Cell Rep. 2017, 19, 2026–2032. [Google Scholar] [CrossRef] [PubMed]
  104. Verhaak, R.G.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98–110. [Google Scholar] [CrossRef] [PubMed]
  105. Papagiannakopoulos, T.; Friedmann-Morvinski, D.; Neveu, P.; Dugas, J.C.; Gill, R.M.; Huillard, E.; Liu, C.; Zong, H.; Rowitch, D.H.; Barres, B.A.; et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 2012, 31, 1884–1895. [Google Scholar] [CrossRef] [PubMed]
  106. Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Williams, S.; Otsuki, A.; Nuovo, G.; Raychaudhury, A.; Newton, H.B.; Chiocca, E.A.; Lawler, S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res. 2008, 68, 9125–9130. [Google Scholar] [CrossRef] [PubMed]
  107. Bracken, A.P.; Helin, K. Polycomb group proteins: Navigators of lineage pathways led astray in cancer. Nat. Rev. Cancer 2009, 9, 773–784. [Google Scholar] [CrossRef] [PubMed]
  108. Bian, E.B.; Li, J.; He, X.J.; Zong, G.; Jiang, T.; Li, J.; Zhao, B. Epigenetic modification in gliomas: Role of the histone methyltransferase EZH2. Expert Opin. Ther. Targets 2014, 18, 1197–1206. [Google Scholar] [CrossRef] [PubMed]
  109. Schonberg, D.L.; Lubelski, D.; Miller, T.E.; Rich, J.N. Brain tumor stem cells: Molecular characteristics and their impact on therapy. Mol. Asp. Med. 2014, 39, 82–101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Rich, J.N.; Eyler, C.E. Cancer stem cells in brain tumor biology. Cold Spring Harb. Symp. Quant. Biol. 2008, 73, 411–420. [Google Scholar] [CrossRef] [PubMed]
  111. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401. [Google Scholar] [CrossRef] [PubMed]
  112. Taylor, M.D.; Poppleton, H.; Fuller, C.; Su, X.; Liu, Y.; Jensen, P.; Magdaleno, S.; Dalton, J.; Calabrese, C.; Board, J.; et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005, 8, 323–335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Vescovi, A.L.; Galli, R.; Reynolds, B.A. Brain tumour stem cells. Nat. Rev. Cancer 2006, 6, 425–436. [Google Scholar] [CrossRef] [PubMed]
  114. Wynder, C.; Hakimi, M.A.; Epstein, J.A.; Shilatifard, A.; Shiekhattar, R. Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nat. Cell Biol. 2005, 7, 1113–1117. [Google Scholar] [CrossRef] [PubMed]
  115. Franzoni, E.; Booker, S.A.; Parthasarathy, S.; Rehfeld, F.; Grosser, S.; Srivatsa, S.; Fuchs, H.R.; Tarabykin, V.; Vida, I.; Wulczyn, F.G. miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6. eLife 2015, 4, e04263. [Google Scholar] [CrossRef] [PubMed]
  116. Lin, Q.; Wei, W.; Coelho, C.M.; Li, X.; Baker-Andresen, D.; Dudley, K.; Ratnu, V.S.; Boskovic, Z.; Kobor, M.S.; Sun, Y.E.; et al. The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nat. Neurosci. 2011, 14, 1115–1117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Mondal, T.; Subhash, S.; Vaid, R.; Enroth, S.; Uday, S.; Reinius, B.; Mitra, S.; Mohammed, A.; James, A.R.; Hoberg, E.; et al. MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat. Commun. 2015, 6, 7743. [Google Scholar] [CrossRef] [PubMed]
  118. Lukiw, W.J. Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 2007, 18, 297–300. [Google Scholar] [CrossRef] [PubMed]
  119. Lukiw, W.J.; Pogue, A.I. Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. J. Inorg. Biochem. 2007, 101, 1265–1269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Geng, L.; Zhang, T.; Liu, W.; Chen, Y. Inhibition of miR-128 Abates Abeta-Mediated Cytotoxicity by Targeting PPAR-gamma via NF-kappaB Inactivation in Primary Mouse Cortical Neurons and Neuro2a Cells. Yonsei Med. J. 2018, 59, 1096–1106. [Google Scholar] [CrossRef] [PubMed]
  121. Tiribuzi, R.; Crispoltoni, L.; Porcellati, S.; Di Lullo, M.; Florenzano, F.; Pirro, M.; Bagaglia, F.; Kawarai, T.; Zampolini, M.; Orlacchio, A.; et al. miR128 up-regulation correlates with impaired amyloid beta(1-42) degradation in monocytes from patients with sporadic Alzheimer’s disease. Neurobiol. Aging 2014, 35, 345–356. [Google Scholar] [CrossRef] [PubMed]
  122. Liu, Y.; Zhang, Y.; Liu, P.; Bai, H.; Li, X.; Xiao, J.; Yuan, Q.; Geng, S.; Yin, H.; Zhang, H.; et al. MicroRNA-128 knockout inhibits the development of Alzheimer’s disease by targeting PPARgamma in mouse models. Eur. J. Pharmacol. 2018, 843, 134–144. [Google Scholar] [CrossRef] [PubMed]
  123. Guerau-de-Arellano, M.; Smith, K.M.; Godlewski, J.; Liu, Y.; Winger, R.; Lawler, S.E.; Whitacre, C.C.; Racke, M.K.; Lovett-Racke, A.E. Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain 2011, 134, 3578–3589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Tan, C.L.; Plotkin, J.L.; Veno, M.T.; von Schimmelmann, M.; Feinberg, P.; Mann, S.; Handler, A.; Kjems, J.; Surmeier, D.J.; O’Carroll, D.; et al. MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 2013, 342, 1254–1258. [Google Scholar] [CrossRef] [PubMed]
  125. Zhou, L.; Yang, L.; Li, Y.J.; Mei, R.; Yu, H.L.; Gong, Y.; Du, M.Y.; Wang, F. MicroRNA-128 Protects Dopamine Neurons from Apoptosis and Upregulates the Expression of Excitatory Amino Acid Transporter 4 in Parkinson’s Disease by Binding to AXIN1. Cell. Physiol. Biochem. 2018, 51, 2275–2289. [Google Scholar] [CrossRef] [PubMed]
  126. Kocerha, J.; Xu, Y.; Prucha, M.S.; Zhao, D.; Chan, A.W. microRNA-128a dysregulation in transgenic Huntington’s disease monkeys. Mol. Brain 2014, 7, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Mao, G.; Ren, P.; Wang, G.; Yan, F.; Zhang, Y. MicroRNA-128-3p protects mouse against cerebral ischemia through reducing p38alpha mitogen-activated protein kinase activity. J. Mol. Neurosci. 2017, 61, 152–158. [Google Scholar] [CrossRef] [PubMed]
  128. Kulshreshtha, R.; Ferracin, M.; Wojcik, S.E.; Garzon, R.; Alder, H.; Agosto-Perez, F.J.; Davuluri, R.; Liu, C.G.; Croce, C.M.; Negrini, M.; et al. A microRNA signature of hypoxia. Mol. Cell. Biol. 2007, 27, 1859–1867. [Google Scholar] [CrossRef] [PubMed]
  129. Watts, M.E.; Williams, S.M.; Nithianantharajah, J.; Claudianos, C. Hypoxia-Induced MicroRNA-210 Targets Neurodegenerative Pathways. Non-Coding RNA 2018, 4, 10. [Google Scholar] [CrossRef] [PubMed]
  130. Saini, H.K.; Griffiths-Jones, S.; Enright, A.J. Genomic analysis of human microRNA transcripts. Proc. Natl. Acad. Sci. USA 2007, 104, 17719–17724. [Google Scholar] [CrossRef] [PubMed]
  131. Rosenberg, T.; Thomassen, M.; Jensen, S.S.; Larsen, M.J.; Sorensen, K.P.; Hermansen, S.K.; Kruse, T.A.; Kristensen, B.W. Acute hypoxia induces upregulation of microRNA-210 expression in glioblastoma spheroids. CNS Oncol. 2015, 4, 25–35. [Google Scholar] [CrossRef] [PubMed]
  132. Agrawal, R.; Pandey, P.; Jha, P.; Dwivedi, V.; Sarkar, C.; Kulshreshtha, R. Hypoxic signature of microRNAs in glioblastoma: Insights from small RNA deep sequencing. BMC Genom. 2014, 15, 686. [Google Scholar] [CrossRef] [PubMed]
  133. Cheng, L.; Bao, S.; Rich, J.N. Potential therapeutic implications of cancer stem cells in glioblastoma. Biochem. Pharmacol. 2010, 80, 654–665. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Agrawal, R.; Garg, A.; Benny Malgulwar, P.; Sharma, V.; Sarkar, C.; Kulshreshtha, R. p53 and miR-210 regulated NeuroD2, a neuronal basic helix-loop-helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment. Int. J. Cancer 2018, 142, 1817–1828. [Google Scholar] [CrossRef] [PubMed]
  135. Bar, I.; Merhi, A.; Abdel-Sater, F.; Ben Addi, A.; Sollennita, S.; Canon, J.L.; Delree, P. The MicroRNA miR-210 is expressed by cancer cells but also by the tumor microenvironment in triple-negative breast cancer. J. Histochem. Cytochem. 2017, 65, 335–346. [Google Scholar] [CrossRef] [PubMed]
  136. Abdullah, A.I.; Zhang, H.; Nie, Y.; Tang, W.; Sun, T. CDK7 and miR-210 co-regulate cell-cycle progression of neural progenitors in the developing neocortex. Stem Cell Rep. 2016, 7, 69–79. [Google Scholar] [CrossRef] [PubMed]
  137. Zeng, L.; He, X.; Wang, Y.; Tang, Y.; Zheng, C.; Cai, H.; Liu, J.; Wang, Y.; Fu, Y.; Yang, G.Y. MicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain. Gene Ther. 2014, 21, 37–43. [Google Scholar] [CrossRef] [PubMed]
  138. Zhang, S.; Chen, S.; Liu, A.; Wan, J.; Tang, L.; Zheng, N.; Xiong, Y. Inhibition of BDNF production by MPP(+) through up-regulation of miR-210-3p contributes to dopaminergic neuron damage in MPTP model. Neurosci. Lett. 2018, 675, 133–139. [Google Scholar] [CrossRef] [PubMed]
  139. Hu, S.; Huang, M.; Li, Z.; Jia, F.; Ghosh, Z.; Lijkwan, M.A.; Fasanaro, P.; Sun, N.; Wang, X.; Martelli, F.; et al. MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation 2010, 122, S124–S131. [Google Scholar] [CrossRef] [PubMed]
  140. Liu, F.; Lou, Y.L.; Wu, J.; Ruan, Q.F.; Xie, A.; Guo, F.; Cui, S.P.; Deng, Z.F.; Wang, Y. Upregulation of microRNA-210 regulates renal angiogenesis mediated by activation of VEGF signaling pathway under ischemia/perfusion injury in vivo and in vitro. Kidney Blood Press. Res. 2012, 35, 182–191. [Google Scholar] [CrossRef] [PubMed]
  141. Alaiti, M.A.; Ishikawa, M.; Masuda, H.; Simon, D.I.; Jain, M.K.; Asahara, T.; Costa, M.A. Up-regulation of miR-210 by vascular endothelial growth factor in ex vivo expanded CD34+ cells enhances cell-mediated angiogenesis. J. Cell. Mol. Med. 2012, 16, 2413–2421. [Google Scholar] [CrossRef] [PubMed]
  142. Fasanaro, P.; D’Alessandra, Y.; Di Stefano, V.; Melchionna, R.; Romani, S.; Pompilio, G.; Capogrossi, M.C.; Martelli, F. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 2008, 283, 15878–15883. [Google Scholar] [CrossRef] [PubMed]
  143. Meng, Z.Y.; Kang, H.L.; Duan, W.; Zheng, J.; Li, Q.N.; Zhou, Z.J. MicroRNA-210 promotes accumulation of neural precursor cells around ischemic foci after cerebral ischemia by regulating the SOCS1-STAT3-VEGF-C pathway. J. Am. Heart Assoc. 2018, 7, e005052. [Google Scholar] [CrossRef] [PubMed]
  144. Huang, L.; Ma, Q.; Li, Y.; Li, B.; Zhang, L. Inhibition of microRNA-210 suppresses pro-inflammatory response and reduces acute brain injury of ischemic stroke in mice. Exp. Neurol. 2018, 300, 41–50. [Google Scholar] [CrossRef] [PubMed]
  145. Ma, Q.; Dasgupta, C.; Li, Y.; Bajwa, N.M.; Xiong, F.; Harding, B.; Hartman, R.; Zhang, L. Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats. Neurobiol. Dis. 2016, 89, 202–212. [Google Scholar] [CrossRef] [PubMed]
  146. Zhao, L.; Zhou, X.Y.; Zhou, X.G.; Cheng, R.; Li, Y.; Qiu, J. Role of miRNA-210 in hypoxic-ischemic brain edema in neonatal rats. Zhongguo Dang Dai Er Ke Za Zhi 2016, 18, 770–774. (In Chinese) [Google Scholar] [PubMed]
  147. Ma, Q.; Dasgupta, C.; Li, Y.; Huang, L.; Zhang, L. MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury. Int. J. Mol. Sci. 2017, 18, 1356. [Google Scholar] [CrossRef] [PubMed]
  148. Lou, Y.L.; Guo, F.; Liu, F.; Gao, F.L.; Zhang, P.Q.; Niu, X.; Guo, S.C.; Yin, J.H.; Wang, Y.; Deng, Z.F. miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. Mol. Cell. Biochem. 2012, 370, 45–51. [Google Scholar] [CrossRef] [PubMed]
  149. Nagaraj, S.; Zoltowska, K.M.; Laskowska-Kaszub, K.; Wojda, U. microRNA diagnostic panel for Alzheimer’s disease and epigenetic trade-off between neurodegeneration and cancer. Ageing Res. Rev. 2019, 49, 125–143. [Google Scholar] [CrossRef] [PubMed]
  150. Sharma, S.; Lu, H.C. microRNAs in neurodegeneration: Current findings and potential impacts. J. Alzheimer Dis. Parkinsonism 2018, 8, 420. [Google Scholar] [CrossRef] [PubMed]
  151. Yang, Z.B.; Chen, W.W.; Chen, H.P.; Cai, S.X.; Lin, J.D.; Qiu, L.Z. MiR-155 aggravated septic liver injury by oxidative stress-mediated ER stress and mitochondrial dysfunction via targeting Nrf-2. Exp. Mol. Pathol. 2018, 105, 387–394. [Google Scholar] [CrossRef] [PubMed]
  152. Banelli, B.; Forlani, A.; Allemanni, G.; Morabito, A.; Pistillo, M.P.; Romani, M. MicroRNA in glioblastoma: An overview. Int. J. Genom. 2017, 2017, 7639084. [Google Scholar] [CrossRef] [PubMed]
  153. Zhao, F.; Qu, Y.; Zhu, J.; Zhang, L.; Huang, L.; Liu, H.; Li, S.; Mu, D. miR-30d-5p plays an important role in autophagy and apoptosis in developing rat brains after hypoxic-ischemic injury. J. Neuropathol. Exp. Neurol. 2017, 76, 709–719. [Google Scholar] [CrossRef] [PubMed]
  154. Han, L.; Zhou, Y.; Zhang, R.; Wu, K.; Lu, Y.; Li, Y.; Duan, R.; Yao, Y.; Zhu, D.; Jia, Y. MicroRNA Let-7f-5p promotes bone marrow mesenchymal stem cells survival by targeting caspase-3 in alzheimer disease model. Front. Neurosci. 2018, 12, 333. [Google Scholar] [CrossRef] [PubMed]
  155. Balzeau, J.; Menezes, M.R.; Cao, S.; Hagan, J.P. The LIN28/let-7 Pathway in Cancer. Front. Genet. 2017, 8, 31. [Google Scholar] [CrossRef] [PubMed]
  156. Kim, J.; Yoon, H.; Chung, D.E.; Brown, J.L.; Belmonte, K.C.; Kim, J. miR-186 is decreased in aged brain and suppresses BACE1 expression. J. Neurochem. 2016, 137, 436–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Chen, C.H.; Sun, L.; Mochly-Rosen, D. Mitochondrial aldehyde dehydrogenase and cardiac diseases. Cardiovasc. Res. 2010, 88, 51–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Oh, S.E.; Park, H.J.; He, L.; Skibiel, C.; Junn, E.; Mouradian, M.M. The Parkinson’s disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress. Redox Biol. 2018, 19, 62–73. [Google Scholar] [CrossRef] [PubMed]
  159. Salimian, N.; Peymani, M.; Ghaedi, K.; Nasr Esfahani, M.H. Modulation in miR-200a/SIRT1axis is associated with apoptosis in MPP(+)-induced SH-SY5Y cells. Gene 2018, 674, 25–30. [Google Scholar] [CrossRef] [PubMed]
  160. Li, L.; Xu, J.; Wu, M.; Hu, J.M. Protective role of microRNA-221 in Parkinson’s disease. Bratisl. Lek. Listy 2018, 119, 22–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Je, G.; Kim, Y.S. Mitochondrial ROS-mediated post-transcriptional regulation of alpha-synuclein through miR-7 and miR-153. Neurosci. Lett. 2017, 661, 132–136. [Google Scholar] [CrossRef] [PubMed]
  162. Song, S.; Lin, F.; Zhu, P.; Wu, C.; Zhao, S.; Han, Q.; Li, X. Extract of Spatholobus suberctus Dunn ameliorates ischemia-induced injury by targeting miR-494. PLoS ONE 2017, 12, e0184348. [Google Scholar] [CrossRef] [PubMed]
  163. Jin, R.; Xu, S.; Lin, X.; Shen, M. MiR-136 controls neurocytes apoptosis by regulating Tissue Inhibitor of Metalloproteinases-3 in spinal cord ischemic injury. Biomed. Pharmacother. 2017, 94, 47–54. [Google Scholar] [CrossRef] [PubMed]
  164. Zhang, P.; Sun, H.; Yang, B.; Luo, W.; Liu, Z.; Wang, J.; Zuo, Y. miR-152 regulated glioma cell proliferation and apoptosis via Runx2 mediated by DNMT1. Biomed. Pharmacother. 2017, 92, 690–695. [Google Scholar] [CrossRef] [PubMed]
  165. Salta, E.; De Strooper, B. microRNA-132: A key noncoding RNA operating in the cellular phase of Alzheimer’s disease. FASEB J. 2017, 31, 424–433. [Google Scholar] [CrossRef] [PubMed]
  166. Kunkanjanawan, T.; Carter, R.L.; Prucha, M.S.; Yang, J.; Parnpai, R.; Chan, A.W. miR-196a ameliorates cytotoxicity and cellular phenotype in transgenic Huntington’s disease monkey neural cells. PLoS ONE 2016, 11, e0162788. [Google Scholar] [CrossRef] [PubMed]
  167. Gonzales, E.D.; Tanenhaus, A.K.; Zhang, J.; Chaffee, R.P.; Yin, J.C. Early-onset sleep defects in Drosophila models of Huntington’s disease reflect alterations of PKA/CREB signaling. Hum. Mol. Genet. 2016, 25, 837–852. [Google Scholar] [CrossRef] [PubMed]
  168. Fu, M.H.; Li, C.L.; Lin, H.L.; Tsai, S.J.; Lai, Y.Y.; Chang, Y.F.; Cheng, P.H.; Chen, C.M.; Yang, S.H. The Potential Regulatory Mechanisms of miR-196a in Huntington’s Disease through Bioinformatic Analyses. PLoS ONE 2015, 10, e0137637. [Google Scholar] [CrossRef] [PubMed]
  169. Hwang, J.Y.; Kaneko, N.; Noh, K.M.; Pontarelli, F.; Zukin, R.S. The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J. Mol. Biol. 2014, 426, 3454–3466. [Google Scholar] [CrossRef] [PubMed]
  170. Wang, C.; Ji, B.; Cheng, B.; Chen, J.; Bai, B. Neuroprotection of microRNA in neurological disorders (Review). Biomed. Rep. 2014, 2, 611–619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  171. Heman-Ackah, S.M.; Hallegger, M.; Rao, M.S.; Wood, M.J. RISC in PD: The impact of microRNAs in Parkinson’s disease cellular and molecular pathogenesis. Front. Mol. Neurosci. 2013, 6, 40. [Google Scholar] [CrossRef] [PubMed]
  172. Junn, E.; Lee, K.W.; Jeong, B.S.; Chan, T.W.; Im, J.Y.; Mouradian, M.M. Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc. Natl. Acad. Sci. USA 2009, 106, 13052–13057. [Google Scholar] [CrossRef] [PubMed]
  173. Parisi, C.; Arisi, I.; D’Ambrosi, N.; Storti, A.E.; Brandi, R.; D’Onofrio, M.; Volonte, C. Dysregulated microRNAs in amyotrophic lateral sclerosis microglia modulate genes linked to neuroinflammation. Cell Death Dis. 2013, 4, e959. [Google Scholar] [CrossRef] [PubMed]
  174. Sun, L.Q.; Guo, G.L.; Zhang, S.; Yang, L.L. Effects of MicroRNA-592-5p on hippocampal neuron injury following hypoxic-ischemic brain damage in neonatal mice—Involvement of PGD2/DP and PTGDR. Cell. Physiol. Biochem. 2018, 45, 458–473. [Google Scholar] [CrossRef] [PubMed]
  175. Liang, L.; Wang, J.; Yuan, Y.; Zhang, Y.; Liu, H.; Wu, C.; Yan, Y. MicRNA-320 facilitates the brain parenchyma injury via regulating IGF-1 during cerebral I/R injury in mice. Biomed. Pharmacother. 2018, 102, 86–93. [Google Scholar] [CrossRef] [PubMed]
  176. Li, X.Q.; Yu, Q.; Tan, W.F.; Zhang, Z.L.; Ma, H. MicroRNA-125b mimic inhibits ischemia reperfusion-induced neuroinflammation and aberrant p53 apoptotic signalling activation through targeting TP53INP1. BrainBehav. Immun. 2018, 74, 154–165. [Google Scholar] [CrossRef] [PubMed]
  177. Wang, G.; Huang, Y.; Wang, L.L.; Zhang, Y.F.; Xu, J.; Zhou, Y.; Lourenco, G.F.; Zhang, B.; Wang, Y.; Ren, R.J.; et al. MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer’s disease. Sci. Rep. 2016, 6, 26697. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Harraz, M.M.; Eacker, S.M.; Wang, X.; Dawson, T.M.; Dawson, V.L. MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc. Natl. Acad. Sci. USA 2012, 109, 18962–18967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Xiong, R.; Wang, Z.; Zhao, Z.; Li, H.; Chen, W.; Zhang, B.; Wang, L.; Wu, L.; Li, W.; Ding, J.; et al. MicroRNA-494 reduces DJ-1 expression and exacerbates neurodegeneration. Neurobiol. Aging 2014, 35, 705–714. [Google Scholar] [CrossRef] [PubMed]
  180. Yang, K.; Yu, B.; Cheng, C.; Cheng, T.; Yuan, B.; Li, K.; Xiao, J.; Qiu, Z.; Zhou, Y. Mir505-3p regulates axonal development via inhibiting the autophagy pathway by targeting Atg12. Autophagy 2017, 13, 1679–1696. [Google Scholar] [CrossRef] [PubMed]
  181. Feng, S.J.; Zhang, X.Q.; Li, J.T.; Dai, X.M.; Zhao, F. miRNA-223 regulates ischemic neuronal injury by targeting the type 1 insulin-like growth factor receptor (IGF1R). Folia Neuropathol. 2018, 56, 49–57. [Google Scholar] [CrossRef] [PubMed]
  182. Pichler, S.; Gu, W.; Hartl, D.; Gasparoni, G.; Leidinger, P.; Keller, A.; Meese, E.; Mayhaus, M.; Hampel, H.; Riemenschneider, M. The miRNome of Alzheimer’s disease: Consistent downregulation of the miR-132/212 cluster. Neurobiol. Aging 2017, 50, 167. [Google Scholar] [CrossRef] [PubMed]
  183. Wang, Q.; Zhan, Y.; Ren, N.; Wang, Z.; Zhang, Q.; Wu, S.; Li, H. Paraquat and MPTP alter microRNA expression profiles, and downregulated expression of miR-17-5p contributes to PQ-induced dopaminergic neurodegeneration. J. Appl. Toxicol. 2018, 38, 665–677. [Google Scholar] [CrossRef] [PubMed]
  184. Xu, L.J.; Ouyang, Y.B.; Xiong, X.; Stary, C.M.; Giffard, R.G. Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp. Neurol. 2015, 264, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Mezache, L.; Mikhail, M.; Garofalo, M.; Nuovo, G.J. Reduced miR-512 and the elevated expression of its targets cFLIP and MCL1 localize to neurons with hyperphosphorylated Tau protein in Alzheimer disease. Appl. Immunohistochem. Mol. Morphol. 2015, 23, 615–623. [Google Scholar] [CrossRef] [PubMed]
  186. Yang, Z.B.; Zhang, Z.; Li, T.B.; Lou, Z.; Li, S.Y.; Yang, H.; Yang, J.; Luo, X.J.; Peng, J. Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke. Clin. Sci. 2014, 127, 679–689. [Google Scholar] [CrossRef] [PubMed]
  187. Chen, X.; Zhang, Y.; Shi, Y.; Lian, H.; Tu, H.; Han, S.; Peng, B.; Liu, W.; He, X. MiR-873 acts as a novel sensitizer of glioma cells to cisplatin by targeting Bcl-2. Int. J. Oncol. 2015, 47, 1603–1611. [Google Scholar] [CrossRef] [PubMed]
  188. Wu, H.; Liu, Q.; Cai, T.; Chen, Y.D.; Liao, F.; Wang, Z.F. MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1. Diagn. Pathol. 2014, 9, 173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  189. Kushwaha, D.; Ramakrishnan, V.; Ng, K.; Steed, T.; Nguyen, T.; Futalan, D.; Akers, J.C.; Sarkaria, J.; Jiang, T.; Chowdhury, D.; et al. A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget 2014, 5, 4026–4039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  190. Wang, L.; Shi, Z.M.; Jiang, C.F.; Liu, X.; Chen, Q.D.; Qian, X.; Li, D.M.; Ge, X.; Wang, X.F.; Liu, L.Z.; et al. MiR-143 acts as a tumor suppressor by targeting N-RAS and enhances temozolomide-induced apoptosis in glioma. Oncotarget 2014, 5, 5416–5427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  191. Guo, Y.; Yan, K.; Fang, J.; Qu, Q.; Zhou, M.; Chen, F. Let-7b expression determines response to chemotherapy through the regulation of cyclin D1 in glioblastoma. J. Exp. Clin. Cancer Res. 2013, 32, 41. [Google Scholar] [CrossRef] [PubMed]
  192. Li, R.Y.; Chen, L.C.; Zhang, H.Y.; Du, W.Z.; Feng, Y.; Wang, H.B.; Wen, J.Q.; Liu, X.; Li, X.F.; Sun, Y.; et al. MiR-139 inhibits Mcl-1 expression and potentiates TMZ-induced apoptosis in glioma. CNS Neurosci. Ther. 2013, 19, 477–483. [Google Scholar] [CrossRef] [PubMed]
  193. Ng, W.L.; Yan, D.; Zhang, X.; Mo, Y.Y.; Wang, Y. Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair 2010, 9, 1170–1175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Ansari, K.I.; Ogawa, D.; Rooj, A.K.; Lawler, S.E.; Krichevsky, A.M.; Johnson, M.D.; Chiocca, E.A.; Bronisz, A.; Godlewski, J. Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. Cell Rep. 2015, 11, 902–909. [Google Scholar] [CrossRef] [PubMed]
  195. Bronisz, A.; Wang, Y.; Nowicki, M.O.; Peruzzi, P.; Ansari, K.; Ogawa, D.; Balaj, L.; De Rienzo, G.; Mineo, M.; Nakano, I.; et al. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res. 2014, 74, 738–750. [Google Scholar] [CrossRef] [PubMed]
  196. Khwaja, S.S.; Cai, C.; Badiyan, S.N.; Wang, X.; Huang, J. The immune-related microRNA miR-146b is upregulated in glioblastoma recurrence. Oncotarget 2018, 9, 29036–29046. [Google Scholar] [CrossRef] [PubMed]
  197. Li, W.; Liu, Y.; Yang, W.; Han, X.; Li, S.; Liu, H.; Gerweck, L.E.; Fukumura, D.; Loeffler, J.S.; Yang, B.B.; et al. MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma. J. Neuro-Oncol. 2018, 136, 63–71. [Google Scholar] [CrossRef] [PubMed]
  198. Choi, J.Y.; Shin, H.J.; Bae, I.H. miR-93-5p suppresses cellular senescence by directly targeting Bcl-w and p21. Biochem. Biophys. Res. Commun. 2018, 505, 1134–1140. [Google Scholar] [CrossRef] [PubMed]
  199. Besse, A.; Sana, J.; Lakomy, R.; Kren, L.; Fadrus, P.; Smrcka, M.; Hermanova, M.; Jancalek, R.; Reguli, S.; Lipina, R.; et al. MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response. Tumour Biol. 2016, 37, 7719–7727. [Google Scholar] [CrossRef] [PubMed]
  200. Wei, F.; Wang, Q.; Su, Q.; Huang, H.; Luan, J.; Xu, X.; Wang, J. miR-373 Inhibits Glioma Cell U251 Migration and Invasion by Down-Regulating CD44 and TGFBR2. Cell. Mol. Neurobiol. 2016, 36, 1389–1397. [Google Scholar] [CrossRef] [PubMed]
  201. Vogel, J.M.; Morse, R.Y.; Goodenow, R.S. A novel H-2K splice form: Predictions for other alternative H-2 splicing events. Immunogenetics 1989, 29, 33–43. [Google Scholar] [CrossRef] [PubMed]
  202. Fan, H.; Yuan, R.; Cheng, S.; Xiong, K.; Zhu, X.; Zhang, Y. Overexpressed miR-183 promoted glioblastoma radioresistance via down-regulating LRIG1. Biomed. Pharmacother. 2018, 97, 1554–1563. [Google Scholar] [CrossRef] [PubMed]
  203. Huang, T.; Alvarez, A.A.; Pangeni, R.P.; Horbinski, C.M.; Lu, S.; Kim, S.H.; James, C.D.; Raizer, J.J.; Kessler, J.A.; Brenann, C.W.; et al. A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat. Commun. 2016, 7, 12885. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. Guo, P.; Yu, Y.; Tian, Z.; Lin, Y.; Qiu, Y.; Yao, W.; Zhang, L. Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4. Int. J. Oncol. 2018, 53, 1591–1600. [Google Scholar] [CrossRef] [PubMed]
  205. Papagiannakopoulos, T.; Shapiro, A.; Kosik, K.S. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008, 68, 8164–8172. [Google Scholar] [CrossRef] [PubMed]
  206. Montalban, E.; Mattugini, N.; Ciarapica, R.; Provenzano, C.; Savino, M.; Scagnoli, F.; Prosperini, G.; Carissimi, C.; Fulci, V.; Matrone, C.; et al. MiR-21 is an Ngf-modulated microRNA that supports Ngf signaling and regulates neuronal degeneration in PC12 cells. Neuromolecular Med. 2014, 16, 415–430. [Google Scholar] [CrossRef] [PubMed]
  207. Bhaskaran, V.; Nowicki, M.O.; Idriss, M.; Jimenez, M.A.; Lugli, G.; Hayes, J.L.; Mahmoud, A.B.; Zane, R.E.; Passaro, C.; Ligon, K.L.; et al. The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma. Nat. Commun. 2019, 10, 442. [Google Scholar] [CrossRef] [PubMed]
  208. Li, N.; Zhang, Y.; Sidlauskas, K.; Ellis, M.; Evans, I.; Frankel, P.; Lau, J.; El-Hassan, T.; Guglielmi, L.; Broni, J.; et al. Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades. Oncogene 2018, 37, 4313–4333. [Google Scholar] [CrossRef] [PubMed]
  209. Fernando, P.; Brunette, S.; Megeney, L.A. Neural stem cell differentiation is dependent upon endogenous caspase 3 activity. FASEB J. 2005, 19, 1671–1673. [Google Scholar] [CrossRef] [PubMed]
Ncrna 05 00020 g001 550
Figure 1. Gene Venn showing microRNA under investigation in selected pathologies of the brain (based on Table 2) (Brain Cancer (BC), Neurodegenerative Disorders (ND) Ischemia (IH)). MiR-21, let-7, miR-210 and miR-128 are common microRNAs.
Figure 1. Gene Venn showing microRNA under investigation in selected pathologies of the brain (based on Table 2) (Brain Cancer (BC), Neurodegenerative Disorders (ND) Ischemia (IH)). MiR-21, let-7, miR-210 and miR-128 are common microRNAs.
Ncrna 05 00020 g001
Table
Table 1. Functional microRNAs deregulated in brain disorders.
Table 1. Functional microRNAs deregulated in brain disorders.
microRNADisordersTarget
miR-9GBMFOXP1, CREB, NF1, STMN1 [41,42,43,44,45]
PD, ADSIRT1, BACE1, BDNF, Bcl-2 [49]
HDREST, CoREST [46]
miR-29GBMSCAP/SREBP-1 [37], PTEN [55]
AD, HDVDAC, BACE [57,58]
PDPTEN [56]
miR-34abcGBMPDGFRA [64]
PDBCL [74], DJ1, Parkin [73]
ADCyclin D1, SORT1 [75,77], p53 [76]
miR-124GBMSCP1, PTPN12, SNAIL2, ROCK1 [85,86,87], IQGAP1, LAMC1, ITGB1 [84], TWIST [87], TEAD1, MAPK14/p38α [88]
PDSOX9, JAGGED1 [89], BIM [90],
HDPTB, REST [91,92]
IschemiaGLT1/EAAT2 [93]
miR-128GBMBMI1, ABCC5, E2F5 [98,101], RTKs, EGFR, PDGFRα [102,104], SUZ12 [106]
ADROS [118], PPARγ/NF-ĸB [119]
PDERK2 [123], AXIN1/EAAT4 [124]
MSBIM1, IL-4, GATA3 [122]
Ischemiap38 MAPK [126]
miR-210GBMHIF1α, HIF3A, VEGF, CAIC [131], NeuroD2 [134]
PDBDNF [145]
IschemiaVEGF [138,139,140], SOCS1-STAT3-VEGF [141], TNFα, IL-1B, IL-6, CCL 2/3 [142], GR [143], occluding, β-catenin [144]. Notch 1 [145]
Table
Table 2. List of microRNAs deregulated in brain disorders.
Table 2. List of microRNAs deregulated in brain disorders.
DisordersmicroRNAs
Brain Cancer (BC)miR-9, miR-21, miR-17–92, Let-7, miR-10b, miR-34a, miR-7, miR-124-3p, miR-124-5p, miR-137, miR-326, miR-99a, miR-524-5p, miR-328, miR-128, miR-101, miR-302–367, miR-143, miR-145, miR-218, miR-93, miR-125b, miR-451, miR-222, miR-339, miR-148a, miR-181d, miR-210, miR-297
Neurodegenerative
Disorders (ND)		miR-7, miR-9, miR-17-p, miR-21, miR-22, miR-26, miR-29, miR-30a-5p, miR-34, miR-101, miR-107, miR-124, miR-128, miR-133, miR-146, miR-153, miR-132, miR-196a, miR-197, miR-210, miR-200a, Let-7, miR-221, miR-494, miR-512
Ischemia (IH)Let-7, miR-19, miR-21, miR-26, miR-30d-5p, miR-34, miR-107, miR-96, miR-124, miR-125b, miR-128, miR-132, miR-136, miR-137, miR-181d, miR-182, miR-200a, miR-210, miR-218, miR-223, miR-320, miR-328, miR-494, miR-592-5p,

Share and Cite

MDPI and ACS Style

Godlewski, J.; Lenart, J.; Salinska, E. MicroRNA in Brain pathology: Neurodegeneration the Other Side of the Brain Cancer. Non-Coding RNA 2019, 5, 20. https://doi.org/10.3390/ncrna5010020

AMA Style

Godlewski J, Lenart J, Salinska E. MicroRNA in Brain pathology: Neurodegeneration the Other Side of the Brain Cancer. Non-Coding RNA. 2019; 5(1):20. https://doi.org/10.3390/ncrna5010020

Chicago/Turabian Style

Godlewski, Jakub, Jacek Lenart, and Elzbieta Salinska. 2019. "MicroRNA in Brain pathology: Neurodegeneration the Other Side of the Brain Cancer" Non-Coding RNA 5, no. 1: 20. https://doi.org/10.3390/ncrna5010020

APA Style

Godlewski, J., Lenart, J., & Salinska, E. (2019). MicroRNA in Brain pathology: Neurodegeneration the Other Side of the Brain Cancer. Non-Coding RNA, 5(1), 20. https://doi.org/10.3390/ncrna5010020

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop