Abstract
Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.
Highlights
Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by recurrent disabling attacks of imbalance, vertigo, nausea and ataxia, typically lasting hours to days [1,2]
Given the number of mutations predicted to disrupt the splicing of CACNA1A in EA2 [4,6,13,14,15,16,17,18,19,26], splicing-targeting approaches, as described in the previous paragraphs, may hold great promise for developing new EA2 therapies
As for spinal muscular atrophy (SMA), where therapies target SMN2 to compensate for a deficiency in survival motor neuron 1 (SMN1), EA2 therapies could regulate alternative splicing (AS) in presynaptic voltage-gated Ca2+ channels (VGCCs) other than CaV 2.1 to compensate for a deficiency in this channel
Summary
Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by recurrent disabling attacks of imbalance, vertigo, nausea and ataxia, typically lasting hours to days [1,2]. For CaV 2.1[EFb], the expression levels do not undergo major developmental changes, being high in most brain regions from the early stages of postnatal development, for CaV 2.1[EFa], the expression levels build up during synapse maturation, presumably contributing to the developmental increase in neurotransmitter release efficiency. As a result, both splice isoforms are expressed at similar levels in most regions of the adult brain [20,21,22,23,25]. After reviewing RNA splicing, AS, and splicing-based therapies developed for other diseases, we will discuss the potential benefits of splicing-based therapies for EA2
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