Abstract
Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments.
Highlights
The Spinocerebellar ataxias (SCA) are a subset of hereditary cerebellar ataxias that are autosomal dominantly transmitted. They are progressive neurodegenerative diseases that share the clinical features of ataxia, which arise from the progressive degeneration of the cerebellum but can affect other connected regions, including the brain stem
A toxic gain of function effect was found to be implicated in SCA8 pathogenesis, with the CTG CAG repeat expansion, which is bidirectionally expressed, causing [CUG]n transcript accumulation of ribonuclear inclusions that localise with the RNA binding protein Mbnl1
Tremendous scientific progress has occurred in the understanding of spinocerebellar ataxia
Summary
The Spinocerebellar ataxias (SCA) are a subset of hereditary cerebellar ataxias that are autosomal dominantly transmitted They are progressive neurodegenerative diseases that share the clinical features of ataxia, which arise from the progressive degeneration of the cerebellum but can affect other connected regions, including the brain stem. In 412 undiagnosed autosomal dominant cerebellar ataxia (ADCA) without known repeat expansion, 59 individuals (14.3%) were found to harbor pathogenic variants [9]. Thirty five of these variants (8.5%) belong to channel genes. We outline the roles of toxic RNA gain-of-function, mitochondrial
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