Repressor Element-1 Binding Transcription Factor (REST) as a Possible Epigenetic Regulator of Neurodegeneration and MicroRNA-Based Therapeutic Strategies

Abstract

Neurodegenerative disorders (NDD) have grabbed significant scientific consideration due to their fast increase in prevalence worldwide. The specific pathophysiology of the disease and the amazing changes in the brain that take place as it advances are still the top issues of contemporary research. Transcription factors play a decisive role in integrating various signal transduction pathways to ensure homeostasis. Disruptions in the regulation of transcription can result in various pathologies, including NDD. Numerous microRNAs and epigenetic transcription factors have emerged as candidates for determining the precise etiology of NDD. Consequently, understanding by what means transcription factors are regulated and how the deregulation of transcription factors contributes to neurological dysfunction is important to the therapeutic targeting of pathways that they modulate. RE1-silencing transcription factor (REST) also named neuron-restrictive silencer factor (NRSF) has been studied in the pathophysiology of NDD. REST was realized to be a part of a neuroprotective element with the ability to be tuned and influenced by numerous microRNAs, such as microRNAs 124, 132, and 9 implicated in NDD. This article looks at the role of REST and the influence of various microRNAs in controlling REST function in the progression of Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) disease. Furthermore, to therapeutically exploit the possibility of targeting various microRNAs, we bring forth an overview of drug-delivery systems to modulate the microRNAs regulating REST in NDD.

Keywords: Alzheimer’s disease; Extracellular vesicles; Huntington’s disease; MicroRNAs; Parkinson’s disease; Repressor element-1 binding transcription factor.

Fig. 1

Mechanism of REST nuclear translocation and inhibition of REST nuclear entry/levels by genetic/drug/miRs-based approaches in HD. Collaboration between HTT, RILP, and dynactin p150Glued* modulates REST nuclear transport. HAP1, in addition to this, joins this complex via binding to HTT. The overall complex cooperates to keep REST within the cytoplasm. REST is kept within the cytoplasm by this overall complex. mHTT dismantles this complex, causing a nuclear elevation of REST. The REST promoter is activated, and the REST target genes are repressed by the very weak interactions between mHTT and HIP1, which boost the nuclear accumulation of HIPPI and HIP1. REST’s binding to HTT was disrupted, which was assisting in the retention of REST in the cytoplasm. Elevated Src and N-cadherin phosphorylation via mGluR5 elevation is the root cause of the REST entry and suppression of REST targets such as SNAP-25 and BDNF. Induction of exon skipping (∆E3) in HD cells by producing antisense oligos (ASOS) targeting the splicing locations of REST e3 causes hindering of the REST nuclear entry. REST and mHTT levels are lowered by direct reduction of endogenous Hsp90. REST and CoREST are both highly repressed by miR-9 and miR-9*, respectively. Moreover, exosomal miR-124 targets REST and miR-132 targets MECP2, which in turn inhibits BDNF. Abbreviations: HD, Huntington’s disease; mHTT, mutant muntingtin; poly Q, polyglutamine; HTT, huntingtin protein; RILP, REST/NRSF-interacting LIM domain protein; Dynactin, P150(Glued) subunit of dynactin; HAP1, HTT-associated protein 1; HIPPI, huntingtin interacting protein 1 (HIP1) protein interactor; SNAP 25, synaptosomal-associated protein 25; SP1, specificity protein; ZF, zinc fingers; ∆E3, exon-3 skipping; ASOS, antisense oligos; STMN2, Stathmin-2; SYN1, Synapsin I; miR-9, microRNA-9-5p; miR-9*, microRNA-9-3p

Fig. 2

Interplay between REST and miR-132/miR-124 (direct interaction, indirect interaction) and miR-124-APOE interplay in Aβ clearance: plausible involvement of microglia. a REST deficiency, direct REST-mediated miR-132, 9 dysregulation, and concurrent miR target deficits in AD (REST loss and concomitant miR-124 upregulation induce AD). In Aβ_1-42 oligomer (green) treated cells, a decrease in REST occurs and reduced nuclear REST translocation is brought on by the switch of APOE3 to APOE4 expression (blue). In the end, REST failure leads to an increase in miR-124 and a decrease in PTPN1, which in turn encourages tau activation. miR-132 elevation was also shown to be a mediator of Sirtuin 1 (SIRT1) suppression after REST loss, which has an impact on longevity and aging. b REST and miR-124/miR-132 both individually influence the CDK5/calpain pathway in AD (REST loss induces AD, miR-124 prevents AD). Aβ_1-42 induced CDK5R1 overexpression brought on by REST loss was shown. REST loss results in p35/CDK5R1 upregulation, which in turn results in calpain mediated CDK5/p25 activation. Hyperactivated results in BACE-1 phosphorylation and enhanced BACE-1 activity. On the other hand, BACE1-AS stabilizes BACE-1 and initializes BACE-1 genesis. miR-132-3p is inhibited by BACE1 antisense RNA (BACE1-AS). By blocking calpain in a route unrelated to REST action, miR-124 upregulation prevents Aβ_1-42 driven CDK5R1 overexpression brought on by REST loss and contemporaneous CDK5 activation. miR-124 entry into the brain by DNA nanoflowers mediated miR-124 entry into the brain also suppresses BACE-1 activity and inhibits Aβ genesis. c The miR-124-APOE interplay in Aβ clearance: plausible involvement of microglia. Following a mild exposure to hydrogen peroxide, BV2 cells showed a decrease in miR-124 and APOE expression as well as an increase in RFX1 protein level. RFX1 inhibits APOE and impairs Aβ clearance. Microglial exosomes with a prominent elevation of miR-124-3p (Exo-124) result in decreased RELA, which in turn prevents APOE inhibition by RELA and proteolytic breakdown of the amyloid protein in damaged hippocampus neurons. Abbreviations: Aβ, amyloid beta; H₂O₂, hydrogen peroxide; APOE, apolipoprotein; CDK5, cyclin-dependent kinase 5; CDK5R1, cyclin-dependent kinase 5 activators 1 (P35); PTPN1, tyrosine-protein phosphatase nonreceptor type 1; Exo-124, microglial exosomes have more miR124-3p; SIRT1, Sirtuin 1; RELA, v-rel avian reticuloendotheliosis; BACE1-AS, BACE1 antisense RNA

Fig. 3

Mechanisms underpinning how REST and miRs interact in PD.REST is typically produced within the nucleus of DA neurons (violet) and inhibited by α-synuclein (brown). Further Lewy bodies (black) disrupt the nuclear accumulation of REST in the dopaminergic neurons and sequester REST in cytoplasm. The impairment of REST ultimately results in the decrement of PGC1-α, which in turn induces faulty mitochondrial function and impairs mitochondrial function and leads to PD (green). miR-124 blocks faulty mitochondrial function by blocking BIM and concomitant BAX translocation to mitochondria. When LPS causes inflammation during PD, the NF-kB-P65 subunit binds to the GLRX1 promoter and suppresses it. However, because miR-132 mediated NURR1 loss during inflammation cannot enlist CoREST and because transcription repression is compromised, NF-kB-p65 on the GLRX1 promoter is not removed as rapidly, resulting in GLRX1 overexpression and PD. REST knockout from astrocytes along with MPTP boost PD associated effects such as decrement in TH level and increase in neuroinflammation. Additionally, UNC0638, an inhibitor of G9a (a REST/CoREST corepressor), promotes GLRX1 overexpression by hindering the NURR1 and CoREST-mediated suppression of GLRX1. Abbreviations: DA, dopamine; PGC1-α, peroxisome proliferator-activated receptor-γ coactivator; miR-124, microRNA-124; BAX, BCL-2-like protein 4; LPS, lipopolysaccharide; GLRX1, glutaredoxin-1; CoREST, REST corepressor 1; BDNF, brain-derived neurotrophic factor; NURR1, nuclear receptor-related 1 protein; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD, Parkinson’s disease; TSA, Trichostatin-A; TH, tyrosine hydroxylase; miR-132, microRNA-132

Fig. 4

Advanced techniques of miR delivery to prevent AD, PD, and HD. a DNA nanoflowers (DFs) promote the long-term availability of miR-124 in circulation as well as its blood-brain penetration and subsequent neuron targeting in AD. Exosomes (Exo-124) from microglial cells exhibit increased miR-124 and reduced Aβ toxicity. Neuron-derived small EVs (sEVs) secreted from neurons treated with GABA raise the miR-132 abundance, whereas lowered miR-132 levels in the glutamate-induced neuronal secretion of sEVs potentially increase Aβ toxicity. Intra-nasal delivery of miRs coated with polymer nanoparticles modified by lectins and wheat germ agglutinin (WGA)-modified PEGPLA nanoparticle with miR-132 (WGA-NPs-miR-132) prevents AD. Through the intranasal route, DEX-124 can be functionally delivered to microglia and prevent their activation. Intracerebroventricular (i.c.v.) administration of biocompatible and trackable polymeric nanoparticles (NPs) loaded with miR-124 en route to the striatum ameliorates PD. b Injection of exosomes derived from astrocytic and adipose-derived stem cells into the HD environment prevents mHTT and HD progression. Abbreviations: DFs, DNA nanoflowers; sEVs, neuron-derived small extracellular vesicles; WGA-NPs-miR-132, wheat germ agglutinin (WGA)-modified PEGPLA nanoparticle with miR-132; DEX-124, extracellular vesicles produced from dendritic cells; ADSC-Exos, adipose-derived stem cells exosome enriched with miR-124; BBB, blood-brain barrier