Abstract
Purpose of Review
This review summarizes recent studies on the molecular mechanisms of RNA-binding proteins (RBPs) that control neurological functions and pathogenesis in various neurodevelopmental and neurodegenerative diseases, including autism spectrum disorders, schizophrenia, Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and spinocerebellar ataxia.
Recent Findings
RBPs are critical players that regulate every step of posttranscriptional modifications of gene expression. Recent genome-wide approaches revealed that many proteins associate with RNA, but do not contain any known RNA-binding motifs. Additionally, many causal and risk genes of neurodevelopmental and neurodegenerative diseases are RBPs. Development of high-throughput sequencing methods has mapped out the fingerprints of RBPs on transcripts and provided unprecedented potential to discover new mechanisms of neurological diseases. Insights into how RBPs modulate neural development are important for designing effective therapies for numerous neurodevelopmental and neurodegenerative diseases.
Summary
RBPs have diverse mechanisms for modulating RNA processing and, thereby, controlling neurogenesis. Understanding the role of disease-associated RBPs in neurogenesis is vital for developing novel treatments for neurological diseases.
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Introduction
Neurodevelopment requires the functions of different proteins at different developmental stages. It involves diverse transcriptional and posttranscriptional events, such as RNA transportation, alternative splicing, stabilization, degradation, and translation. RNA-binding proteins (RBPs) are critical in regulating these processes (Fig. 1). Dysfunction of RBPs in the early stages of neural system development may affect neuronal migration, synaptic plasticity, and behavioral functions, which eventually lead to neurodevelopmental and neurodegenerative diseases [1].
Overview of RBPs regulating mRNA life cycle. The RBPs discussed in the review are marked with their involvement in posttranscriptional processes. Note that the proteins in color are the proteins that are associated with ASD (red), SCZ (purple), ALS/FTD (blue), and SCA (green)
Autism spectrum disorders (ASD) and schizophrenia (SCZ) are two major neurodevelopmental disorders with strong genetic components. Multiple risk genes for ASD and SCZ encode RBPs. RNA processing defects are observed in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), spinocerebellar ataxia (SCA), and Alzheimer’s disease (AD) [2,3,4,5,6,7,8,9,10]. Thus, we will focus on their diverse functions in regulating RNAs as a variety of etiologies of neurodevelopmental and neurodegenerative diseases.
RBPs in ASDs
FMR1
The neurodevelopmental disorder, fragile X syndrome (FXS), features intellectual deficits and autistic behaviors [11]. FXS is the well-known leading monogenic cause of ASD [12]. The increased trinucleotide repeats at the 5′ untranslated region of FMR1 lead to a decrease of fragile X mental retardation protein (FMRP). Local translation at the synapse is important for neuronal plasticity [13]. As an RBP, FMRP modulates mRNA localization and local translation at the synapse [14]. It represses polypeptide elongation of protein synthesis by stalling polyribosomes [15]. Loss-of-function of FMR1 significantly affects local protein translation and impairs plasticity. In addition, FMR1 serves as a sequence- and context-dependent N6-methyladenosine (m6A) reader, indicating that the m6A modification regulates mRNA stability [16].
The FXS mouse (Fmr1−/y) shows hyperactive ERK and mTOR signaling. Chronic metformin treatment selectively downregulates the ERK and mTOR signaling pathway and rescues core autistic phenotypes in this mouse model [12]. Metformin treatment also corrects the phenotypes of increased spine density and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), providing an exciting drug target for FXS. Using translating ribosome affinity purification (TRAP) and RNA-seq, excessively translating mRNAs were identified in CA1 pyramidal neurons of the Fmr1−/y mouse model [17]. The muscarinic acetylcholine receptor 4 (M4) is excessively translated and consequently suppresses mGluR-induced LTD of synaptic transmission. VU0152100, a positive allosteric M4 modulator, enhances the cholinergic effects on M4, which significantly reduce the audiogenic seizures [17], suggesting a potential pathway to reverse FXS-associated phenotypes.
ELAV-Like RBPs
Neuronal ELAV-like RBPs are involved in several neurological disorders [17]. The combination of crosslinking-immunoprecipitation and RNAseq (CLIP-seq) has identified more than 8000 targets that bind to ELAV-like RBPs. They regulate splicing and abundance of bound RNAs [8]. Knockdown of ELAVL2 in primary human neurons alters mRNA alternative splicing, including RBFOX1 and FMR1, which are well-known ASD risk genes [18]. The CUGBP ELAV-like family member 4 (CELF4) gene encodes an RBP. Haploinsufficiency of CELF4 was found in ASD patients [19]. Similarly, CELF4 mutant mice show complex seizure disorders [20]. CELF4 regulates excitatory neurotransmission by stabilizing mRNA and supporting synaptic local translation [21]. It regulates about 30% of potential ASD risk genes at pre- and postsynaptic sites.
RBFOX1
RBFOX proteins are a family of RNA-binding proteins that contain a single high-affinity RNA recognition domain. RBFOX proteins bind to UGCAUG motifs to regulate RNA processing in neurons, muscle, and heart [22]. RBFOX1 has been associated with neurodevelopmental disorders, such as ASD and epilepsy [23, 24]. Alternative splicing of RBFOX1 generates different protein isoforms localized to either the nucleus or cytoplasm. The nuclear isoform regulates mRNA splicing. Downregulation of nuclear RBFOX1 delays neuronal migration in the brains of embryonic day 14.5 mice [25]. CLIP-seq shows that targets of Rbfox1 in mouse brains enriched in regulating brain development and ASD risk genes [26]. Unlike nuclear RBFOX1, cytoplasmic RBFOX1 predominantly regulates mRNA stability and translation. CLIP-seq results at single-nucleotide resolution indicate that cytoplasmic RBFOX1 binds to 3′-UTR of mRNA targets and increases their abundance [23]. The Rbfox1-bound genes control synaptic activity and calcium signaling.
Exon Junction Complex
The exon junction complex (EJC) is an RNA-binding protein complex that controls pre-mRNA splicing, maturation, translation, and nonsense-mediated mRNA decay (NMD) [27]. The core protein components are eIF4AIII, MAGOH, RBM8A, and BTZ [28, 29]. Pre-mRNA splicing plays an important role in the development of the central neural system, and multiple NMD factors are known to associate with neurodevelopmental disorders [30].
RBM8A is highly expressed in the neural progenitor cells (NPCs) of the subventricular zone at embryonic brain. Downregulation of RBM8A at embryonic day 13 promotes the neuronal migration in the neocortex and decreases the proliferation of NPCs. Upregulation of RBM8A suppresses the neuronal migration and increases the NPC dividing [31]. Consistently, haploinsufficiency of eIF4AIII, MAGOH, and RBM8A in NPCs of the dorsal telencephalon reduces cortical area and volume of mouse brains [32,33,34]. Conditional deletion of TP53 in NPCs reverses the microcephaly phenotype in the embryonic state [32]. In adult mice, abnormal RBM8A expression in the dentate gyrus leads to anxiety behaviors [35].
NMD is an mRNA surveillance mechanism that eliminates mRNAs containing premature termination codons. UPF1, UPF2, UPF3A, and UPF3B are required for activation of NMD in eukaryotes [36]. UPF3B mutations were identified in patients with ASD, SCZ, or attention-deficit hyperactivity disorder [37,38,39,40]. Knockdown of UPF3B increases proliferation of NPCs and decreases primary axon growth. UPF3B-null mice have fewer dendritic spines and less neural activity. The mutant UPF3B mice are deficient in the prepulse inhibition and fear learning tests [41]. Interestingly, UPF3A, an assumed redundant paralog of UPF3B, has an opposing function against the NMD pathway [42]. In the nervous system, besides regulating NMD, UPF1 facilitates mRNA transport and local translation for synaptic plasticity [43]. Downregulation of UPF1 decreases MAP1B mRNA in neurites. STAU2, another RBP, physically interacts with UPF1 to regulate mRNA transportation. Thus, RBPs controlling NMD are important in protecting neuronal development from inaccurate mRNA splicing and incorrect synaptic development.
Methyl-DNA-Binding Proteins
Epigenetic regulators, such as MECP2 and DNA methyl-transferases (DNMTs), contain a well-characterized methyl-DNA-binding domain (MBD) and modulate DNA methylation. Abnormal copies of MECP2 affect neuronal development and lead to neurodevelopmental disorders. MECP2 deletion causes Rett’s syndrome [44], whereas MECP2 duplication leads to similar autistic behaviors and intellectual disability. Conditionally, overexpressed MECP2 in a mouse model can be behaviorally corrected by removing one MECP2 allele or using antisense oligonucleotides to silence MECP2 [45], suggesting that gene dosage is important for the brain development. Intriguingly, some MBD proteins and DNMTs, including MECP2, interact with RNA and form an RNA protein complex [46]. The RNA-binding motifs in these proteins are different from their MBDs. These data suggest that MBD-containing proteins and DNMTs associate with RNAs to participate in DNA methylation [47]. MBD1 and MECP2 dysfunction affect adult neurogenesis and the hippocampal functions [48,49,50].
Other RBPs in ASDs
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of RBPs that control variant transcriptional and translational events. Abnormalities of hnRNPs are associated with different neurological diseases and cancers [51]. Missense mutation of HNRNPH2, which localizes in the X chromosome, associates with autistic behaviors and ataxia in females [52]. HNRNPU deletion was reported in patients with infantile spasms, seizures, and brain malformation [53, 54].
The growth cone responds to axonal guidance cues to reach a targeted region and form synapses. This process involves local mRNA translation to generate rapidly appropriate responses. The RBPs, hnRNPK and PCBP1, associate with mRNA and Mena (ENAH), an actin-regulatory protein, to form an RNP complex [55]. CLIP data show that Mena-bound mRNAs modulate axon guidance. DYRK1A (dual specificity tyrosine phosphorylation regulated kinase 1A), a Down syndrome and ASD risk gene, is guided by the Mena complex regulating the synaptic local translation.
Janus kinase and microtubule-interacting protein 1 (JAKMIP1) is an RBP that is involved in RNP translation. JAKMIP1 is highly expressed in glutamatergic neurons in developmental brains [56]. Differential expression of JAKMIP1 has been observed in ASD patients [57]. Protein interactome analysis indicates that JAKMIP1’s binding partners participate in translational regulation [58]. Jakmip1 knockout mice show autistic behaviors, such as social deficits, repetitive behavior, and impaired vocalization [58]. Translation initiation factors, such as EIF4E, regulate local translation in the synapse. De novo mutations of EIF4E have been associated with autistic behaviors [59].
RBPs in SCZ
Disrupted in Schizophrenia 1
SCZ is a devastating mental disorder affected by genetic risks. Disrupted in Schizophrenia 1 (DISC1) was first identified in a big Scottish family with high incidences of mental diseases [60]. The chromosomal translocation within the DISC1 gene locus is associated with SCZ [61]. DISC1 associates with many proteins and is important in neurogenesis and neural plasticity [62, 63]. It modulates the Wnt pathway and NPC proliferation and neuronal migration/differentiation by inhibiting GSK3β activity [64,65,66,67,68]. Interactome screens indicate that DISC1 physically interacts with several RBPs [69]. Its targets involve RNA-transporting granules and synaptic plasticity, such as the ITPR1 gene.
ZNF804A
ZNF804A was the first SCZ risk gene reaching genome-wide signifcance in a genome-wide association study (GWAS) [70]. Several follow-up GWASs replicated that result and also confirmed the association of rs1344706 with SCZ in different populations [71,72,73,74,75,76,77,78,79]. In addition to common variants, the SGENE-plus consortium reported rare copy number variants (CNVs) at the ZNF804A locus in psychotic patients, including a deletion in a SCZ patient, a deletion in a patient with an anxiety disorder, and a duplication in a BD patient [73], but none in controls. Interestingly, chromosome duplication, deletion, inversion, and translocation at the ZNF804A locus were found in patients with autism [80, 81] and developmental delay [82, 83]. Consistent with the reproducible genetic association of risk SNP in ZNF804A with SCZ, neuroimaging and neuropsychological studies provide mounting evidence that ZNF804A risk allele modulates human brain structures and functions [84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110].
ZNF804A contains a zinc-finger domain that shows both DNA- and RNA-binding ability. Although it has been proposed to function as a transcription factor [111], using RNA immunoprecipitation sequencing (RIP) and interactome analysis, we found that ZNF804A binds to RNAs [112]. ZNF804A is highly expressed in the prenatal central nerve system. Knockdown of ZNF804A affects translation, as well as neural migration toward the neocortex in mouse embryonic stage [112]. Suppression of ZNF804A expression in human NPCs and primary rat cortical neurons reduces neurite formation and dendritic spine formation [113], supporting the important function of ZNF804A in brain functions.
Quaking
Quaking (QKI) is a member of the signal transduction and activation of RNA (STAR) protein family and the HNRNPK homology (KH)-type family [114]. QKI binds to its downstream mRNAs carrying a conserved QKI response element (QRE). QKI regulates several RNA processes, including alternative splicing, micro-RNA processing, and mRNA stabilization and translation. Differential splicing of QKI mRNA produces several isoforms. Decreased QKI-7 and QKI-7b were observed in 55 SCZ patients [114]. These isoforms are regulated by HNRNPC1/C2 [115]. QKI isoforms are also expressed in astrocytes. Downregulation of QKI-7 in astrocytes decreases glial fibrillary acidic protein (GFAP) expression. A typical antipsychotic medication, haloperidol, increases QKI-7 and GFAP expression, suggesting that QKI-7 coordinates with GFAP to regulate the function of astrocytes [116]. This study proposes a new potential link of RNA processing with SCZ.
A recent GWAS identified 108 genetic loci associated with SCZ [78]. SCZ shares many risk genes with intellectual disability and ASDs. Interestingly, de novo mutations in SCZ enriched in glutamatergic postsynaptic proteins related to activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes. Many transcripts of these complexes are targets of FMRP [117]. Interestingly, FMRP is also a substrate of glycogen synthase kinase 3β (GSK3β) [118]. Inhibition of GSK3β showed antipsychotic effects and mood stabilization.
RBPs in ALS/FTD
ALS and FTD are two diseases with similar symptoms and pathogenesis [119]. Recent evidence indicates that disrupting RNA homeostasis is a leading cause of ALS/FTD [120]. Mutations in several RBPs have been identified in ALS/FTD patients.
STAU1
Staufen 1 (STAU1) is an RNA-binding protein responsible for RNA transportation, localization, translation, and the ribonucleoprotein formation [121]. Gershoni-Emek et al. observed altered localization of synaptic STAU1 in an ALS SOD1G93A mouse model, probably due to interrupted retrograde transportation from the synapses [122].
TDP-43
TAR DNA-binding protein 43 (TDP-43, also called TARDBP) is a causal gene for ALS [123]. It encodes an RBP involved in transcription, mRNA splicing, stability, and transportation [124]. Cytoplasmic mislocalization and decreased nuclear expression are associated with TDP-43 mutations. Both mislocalization and downregulation of expression contribute to the cellular toxicity [125, 126]. Though the protein has been associated with ALS for almost two decades, until recently, studies revealed that an oligomeric form of TDP-43 is functional in the nucleus, and this state is essential for its role in RNA metabolism [127]. Additionally, TDP-43 has been reported to regulate ER-mitochondria communication and Ca2+ homeostasis, probably through regulating GSK3β signaling pathway [128]. Using motor neurons derived from human-induced pluripotent stem (iPS) cells, Alami et al. reported that anterograde axonal transportation of mRNAs was reduced in ALS-causing mutations of TDP-43 [129].
Fused in Sarcoma
Fused in sarcoma (FUS), another ALS/FTD risk gene, shares many common pathophysiological characteristics with TDP-43 [123]. They are both involved in RNA processing and neuronal development [130]. Specifically, FUS binds to nascent mRNA and modifies alternative splicing [130]. A recent microarray study suggested that these two proteins share some downstream targets, including splicing and expression regulation [131]. In fibroblasts derived from an ALS patient, FUS formed nuclear aggregates [132]. Patel et al. reported that FUS undergoes a dynamic liquid-like phase transition in vivo, and converted to aggregates upon aging. This transition to aggregates is accelerated with the disease-related mutations in prion-like domains [133]. This could be the mechanism for other age-related diseases involving proteins carrying prion-like domains. Later in the same year, Murakami and colleagues reported a similar phenotype that mutant FUS generates irreversible hydrogels from liquid droplets [134]. ALS-associated FUS mutations often show higher cytoplasmic expression than wild-type controls [135], and the nuclear-localization of FUS does not seem to be required for protein aggregation and neuronal toxicity [136].
When ALS-associated FUS mutant aggregates, other ALS-associated RNA-binding proteins are sequestered in the same complex, including SMN1, hnRNPA1, hnRNPA2, and STAU-1 [134, 137]. Using an in vitro fluorescent molecule tracking assay, Murakami et al. reported that irreversible FUS aggregates trap cargo RNPs and lead to cellular toxicity. Especially among the affected proteins, SMN1 is the major causal gene for spinal muscular atrophy (SMA). Sun et al. reported that the interaction of FUS with SMN protein is increased in ALS-associated FUS mutants [138]. At the same time, the mutated FUS has reduced interaction with U1-snRNP, through which it affects global mRNA splicing [138, 139]. FUS also regulates translation. Yasuda et al. observed that FUS promotes translation preferentially within cell protrusions, and the translation process is not halted by FUS-positive granules [140]. Fragmentation of the Golgi apparatus has been observed in ALS [141, 142], and FUS disease mutation induces Golgi fragmentation [143]. Although FUS is associated with both ALS and FTD, Suárez-Calvet and colleagues identified a difference: mono-methylated arginines occur exclusively in FTLD-FUS mutations, which makes the protein to bind tightly to the nuclear import receptor, transportin-1, but not in ALS-FUS mutations [144].
C9ORF72
The hexanucleotide “GGGGCC” repeat expansion in the noncoding region of the C9ORF72 gene is another common genetic cause for ALS/FTD. Donnelly et al. reported an alteration in gene expression profiles and sequestration of a GGGGC binding RBP, ADARB2, in nuclear aggregates of patient-derived iPS cells with C9ORF72 repeats [145]. Other ALS-associated RBPs, including FUS, TDP-43, and HNRNPA1, were not identified in the same complexes [145]. However, another study did find inclusion of other RBPs, including SF2, SC35, and HNRNPH. HNRNPH was identified as a binding partner to the hexanucleotide expansion [146]. Aggregation results in increased sensitivity to glutamate toxicity [145] and enhanced apoptosis [146]. Besides interrupting RNA processing, ATM-mediated DNA repair was disrupted by the expansion, suggesting another possible cause of neurodegeneration by repeat expansion [147]. Unbiased yeast screening revealed that karyopherins and other nucleocytoplasmic transport proteins are involved in the cytotoxicity [148]. Several potential drug targets have been reported that might help prevent neurodegeneration-associated deficits, including inhibiting SRSF1-dependent nuclear export of C9ORF72 repeat transcripts [149] and antisense intervention [145].
GLE1
Recent exome screening studies linked mutations in GLE1 with ALS [150]. GLE1 expresses two isoforms in human cells, GLE1A and GLE1B [151]. GLE1A regulates translation and is localized to stress granules (SG) upon stress and regulates SG assembly and disassembly [152]. GLE1B is an mRNA export factor associated with nuclear pore complex [151, 153]. GLE1 mutations lead to dysregulation at nuclear pore complexes and cause human lethal congenital contracture syndrome-1 (LCCS1) [154, 155]. In zebrafish, Gle1 knockout results in defective Schwann cell development [156]. The ALS-linked GLE1 allele was reported to encode a protein that has the function of both GLE1A and GLE1B, which may affect the normal regulatory roles of GLE1 [157].
RBPs in SCA
SCAs are a group of over 35 progressive neurodegenerative diseases. At least six of them (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are caused by a polyglutamine expansion encoded by CAG repeats [158]. Two of the risk proteins, polyglutamine expansion within the ataxin-1 protein (ATXN1) and ATXN2, causing SCA1 and 2, respectively, have been identified as RBPs.
ATXN1
The ATXN1 mutation causes SCA1 [159]. The binding ability of this RBP is disrupted by the expanded polyglutamine [160]. ATXN1 regulates neuronal proliferation in vitro and in vivo [161, 162]. By modulating the GSK3β-mTOR pathway, ATXN1 regulates energy homeostasis in the mouse cerebellum [163]. On the other hand, the RAS-MAPK-MSK1 pathway modulates ATXN1 protein level and its associated toxicity [164]. Meanwhile, ATXN1 expression level is negatively regulated by PUMILIO1 (PUM1), which is also an RBP, by modulating ATXN1 RNA stability [165]. By increasing the expression of ATXN1, Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration [165]. Transcriptome profiles of the cerebellum in ATXN1 transgenic mice at several ages and genotypes revealed that upregulation of cholecystokinin (CCK) may play a protective role against Purkinje cell death [166]. Intracellular expression of HMGB1 prolongs lifespan in mutant ATXN1 knock-in mice by repairing mitochondrial DNA damage, which may serve as a potential treatment for SCA1 [167].
ATXN2
Abnormal polyglutamate expansion in ATXN2 results in SCA2 [168, 169] and ALS [170]. ATXN2 regulates metabolism through modulating the mTOR pathway [171,172,173]. It belongs to the like-Sm (LSm) protein family that regulates multiple aspects of RNA metabolism [174]. It directly interacts with poly(A)-binding protein, cytoplasmic 1 (PABPC1), and possibly regulates translation and mRNA stability partly through its binding partners [175, 176]. Meanwhile, PAR-CLIP revealed that ATXN2 also targets genes in a PABPC1-independent manner and helps to maintain mRNA stability, including genes involved in posttranscriptional processes and metabolic processes [177]. For example, TDP-43 is targeted by ATXN2 [177]. Crossing Ataxin-2 knockout mice to TDP-43 transgenic mice showed drastic reduction in TDP-43 aggregation [178]. In cell culture, ATXN2 carrying an intermediate length of polyglutamate repeats promotes mutant FUS translocation and stimulates Golgi fragmentation and apoptosis caused by mutant FUS [143]. The same ATXN2 mutant also enhances neuronal toxicity caused by C9ORF72 depletion [179]. Mitochondria dysfunction is associated with ALS [180]. ATXN2 was identified as a transcriptional regulator upstream of PINK1, a key regulator for mitochondrial stress response [181]. By positively regulating the translation of a circadian rhythm gene, Period (PER), ATXN2 modulates circadian cycle in Drosophila [182, 183]. Antisense oligonucleotides (ASO) of Ataxin-2 effectively improve motor functions in several SCA mouse models, suggesting ASO as a potential treatment for ATXN2-associated human neurodegenerative diseases [178, 184].
RNA Metabolism in AD
The neurofibrillary tangle caused by microtubule-associated protein, tau, is a well-known pathological feature of AD. Though there is still a controversy on whether tau is an RBP or not, it has been reported decades ago that RNA facilitates the formation of paired helical filaments of tau [185]. A study using a Tau-knock-out mouse model suggests that RNA-integrity in neurons is affected under heat shock with tau deficiency [186]. Recently, using PAR-iCLIP, Zhang et al. found that the major associated RNAs of tau are tRNAs [187]. Intriguingly, mixing tau and RNA in vitro created dynamic liquid droplets, which may be the mechanism underlying tau pathology [187]. Besides direct association with RNA, tau interacts with RBPs. Vanderweyde et al. reported that TIA-1 modulates tau pathology, and synergistically, they promote neuronal death [188]. Besides tau, other AD-associated proteins have been suggested to be regulated by RNA. Faghihi et al. reported that the concentration of β-secretase 1 (BACE1) antisense RNA is elevated in both postmortem human brains and Tg19959 mouse [189]. The elevation was associated with BACE1 mRNA stability and Aβ accumulation [189]. Knockdown of this RNA transcript induces neuronal differentiation [190].
Conclusion
In the human genome of ~ 20,000 protein coding genes, about 7.5% directly associate with RNA and regulate different RNA processes. Many RBPs are implicated in human diseases and only a small fraction of RBPs are summarized in this review (Table 1). The rapid development of next-generation sequencing-based methods, such as RIP- and CLIP-based methods, ribosome profiling, in vivo RNA secondary structure profiling, and small and long RNA-seq, will help define the regulation of each RBP in the whole RNA network. However, many details of RNA regulatory mechanisms and their disease relevance remain to be determined. These studies will reveal novel targets and pathways that potentially facilitate new therapeutic development.
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We thank Young Investigator Grant of NARSAD and Scientist Development Grant of American Heart Association for Yingwei Mao. This work is supported by NIH 1R21MH108983.
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Zhou, Y., Dong, F. & Mao, Y. Control of CNS Functions by RNA-Binding Proteins in Neurological Diseases. Curr Pharmacol Rep 4, 301–313 (2018). https://doi.org/10.1007/s40495-018-0140-7
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DOI: https://doi.org/10.1007/s40495-018-0140-7