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Splicing and neurodegeneration: Insights and mechanisms

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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
Splicing cycle and regulatory sequences. (a) Steps of mRNA splicing cycle. Boxes = exons, line = introns. Common regulatory sequences in the pre‐mRNA are shown in red. U designates small nuclear ribonucleoprotein (snRNP) complexes. (b) Recognition of regulatory sequences by snRNP complexes and sequence‐specific RNA binding proteins. 70K=U1 70K protein, ESE: exon splicing enhancer, U2AF: U2 snRNP‐associated factors, SR: serine–arginine‐rich proteins
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RNA‐binding proteins involved in amyotrophic lateral sclerosis (ALS). Domain structures of proteins involved in ALS that is discussed in this review
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Antisense‐oligonucleotide therapeutic for spinal muscular atrophy. SMN1 encodes nearly 100% of all SMN protein in a cell as the SMN2 gene contains a naturally occurring mutation that results in aberrant splicing and the production of an unstable protein. In patients with SMA, the SMN1 gene is missing thus most functional protein is absent. Nusinersen/Spinraza ASO binds downstream of Exon 7 blocking a splicing silencer sequence resulting in improved inclusion of Exon 7 and production of more functional SMN protein
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RNA in Disease and Development > RNA in Disease
RNA in Disease and Development > RNA in Development
RNA Processing > Splicing Regulation/Alternative Splicing

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