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

Abstract

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.

Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder

“…30 , 31 ). Overall, 10 oligonucleotide drugs, six of which are SSOs, have been approved by FDA 32 , 33 and others are in late stages of clinical trials, e.g., Sepofarsen targeting a commonly occurring deep intronic CEP290 variant that causes Leber congenital amaurosis 34 . Together with FDA approved Milasen, a personalised SSO that silences a cryptic splice site introduced by insertion of a retrotransposon in CLN7 gene, causing a rare, fatal neurodegenerative Batten’s disease in a single patient 35 , our findings support further studies to assess the potential of SSOs for treating patients with the TIMMDC1 c.597-1340A>G variant, and cognate variants.…”

Mechanisms of disease-associated SINE-VNTR-Alus

“…Antisense oligonucleotides (AOs) are single-stranded synthetic nucleic acid analogues that can be designed to target specific sequences to modulate gene expression and several have been licensed to treat diseases such as Duchenne muscular dystrophy and spinal muscular atrophy. 82 AOs have been designed to target missplicing caused by two SVA insertions, one of which (milasen) was approved by the Food and Drug Administration and expedited institutional review board to be administered by an intrathecal bolus injection to the patient it was designed for in a "n-of-1" situation. 48,52,83 AOs were designed to restore translation of the fulllength fukutin protein to correct the missplicing caused by the SVA insertion in the 3 ′ UTR of the FTKN gene that causes FCMD.…”

RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

“…mRNA splicing is emerging as a crucial mechanism for maintaining neuronal transcriptome complexity, shaping neuronal structure, function, and differentiation processes [10][11][12]. Perturbations of the essential association between cis-acting elements and splicing motifs result in splicing defects, potentially resulting in neurological disorders or neurodegenerative disease [13].…”

“…Effect on neurodegenerative diseases: Alternative splicing also regulates the expression of different isoforms of α-synuclein, the main component of Lewy bodies and a hallmark of Parkinson's disease (PD) [16]. Similarly, the ratio of alternatively spliced products of the tau gene product MAPT [13], namely 3R tau (formed upon exclusion of exon 10) and 4R tau (formed upon inclusion of exon 10) contribute to another well-known neurodegenerative disorder, Alzheimer's disease (AD). Some recent studies have also highlighted alternative splicing and splicing defects as contributory mechanisms of different neurodegenerative diseases [17].…”