Splicing and neurodegeneration: Insights and mechanisms

Abstract

Splicing is the global cellular process whereby intervening sequences (introns) in precursor messenger RNA (pre‐mRNA) are removed and expressed regions (exons) are ligated together, resulting in a mature mRNA transcript that is exported and translated in the cytoplasm. The tightly regulated splicing cycle is also flexible allowing for the inclusion or exclusion of some sequences depending on the specific cellular context. Alternative splicing allows for the generation of many transcripts from a single gene, thereby expanding the proteome. Although all cells require the function of the spliceosome, neurons are highly sensitive to splicing perturbations with numerous neurological diseases linked to splicing defects. The sensitivity of neurons to splicing alterations is largely due to the complex neuronal cell types and functions in the nervous system that require specific splice isoforms to maintain cellular homeostasis. In the past several years, the relationship between RNA splicing and the nervous system has been the source of significant investigation. Here, we review the current knowledge on RNA splicing in neurobiology and discuss its potential role and impact in neurodegenerative diseases. We will examine the impact of alternative splicing and the role of splicing regulatory proteins on neurodegeneration, highlighting novel animal models including mouse and zebrafish. We will also examine emerging technologies and therapeutic interventions that aim to “drug” the spliceosome. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development

Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

“…In addition to proteins involved in translation, we surprisingly identified a pronounced regulation of splicing-associated proteins in our proteomics analysis. Defects in splicing have been closely linked to neurodegenerative diseases such as ALS [ 49 , 50 ]. We therefore investigated whether the attenuation of axonal degeneration by AAV.ULK1.DN might additionally be mediated by an effect on splicing.…”

Translational changes induced by acute sleep deprivation uncovered by TRAP-Seq

“…Alternative splicing of transcripts may affect mRNA stability, RNA localization, or protein interactions (reviewed in [74,75]). Changes in alternative splicing or splicing dysregulation have been observed in neurodegenerative diseases [75][76][77]. However, it is difficult to determine whether alternatively spliced transcripts are translated.…”

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

“…In zebrafish, knockdown of U1 snRNP components caused the truncation of the motor neuron axon, and similar phenotypes were observed by knockdown of FUS and survival motor neuron protein (SMN) [135]. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by synaptic dysfunction, amyloid plaques, and neurofibrillary tangles formed by the aggregation of Tau protein encoded by the microtubule associated protein tau (MAPT) gene [138]. In the brains of patients with AD, increased aggregation of insoluble U1 snRNP was identified by proteomic analysis [137].…”

“…RNA-seq analysis in human postmortem brain with TDP-43 mutations revealed cryptic exon expression [56]. This feature is common in ALS/FTD patients [56,138]. Whether the mislocalization of spliceosomal components induced by the aggregation of FUS or TDP-43 directly contributes to the cryptic splicing is still unknown.…”