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Neurodegenerative diseases:a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration 2021年第2期10卷 195-212页

作者： Dunhui Li Craig Stewart McIntosh Frank Louis Mastaglia Steve Donald Wilton May Thandar Aung-Htut Centre for Molecular Medicine and Innovative Therapeutics Health Futures InstituteMurdoch UniversityPerthWestern AustraliaAustralia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaPerthWestern AustraliaAustralia

Precursor messenger RNA(pre-mRNA)splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions(introns)and ligates coding regions(exons)into a continuous message(mature mRNA).This process is highly regulated and can be highly flexible through a process known as alternative splicing,which allows for several transcripts to arise from a single gene,thereby greatly increasing genetic plasticity and the diversity of proteome.Alternative splicing is particularly prevalent in neuronal cells,where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis,migration and synaptic function.The continuous changes in splicing patterns and a high demand on many cis-and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects.The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function.Several of the most common neurodegenerative diseases involve some form of splicing defect(s),such as Alzheimer’s disease,Parkinson’s disease and spinal muscular atrophy.Our growing understanding of RNA splicing has led to the explosion of research in the field of Splice-switching antisense oligonucleotide therapeutics.Here we review our current understanding of the effects alternative splicing has on neuronal differentiation,neuronal migration,synaptic maturation and regulation,as well as the impact on neurodegenerative diseases.We will also review the current landscape of Splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

关键词： Neurodegenerative diseases Parkinson’s disease Alzheimer’s disease Alternative splicing Splicing defects Antisense oligonucleotides Splice-switching Disease-modifying treatment

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