Spinocerebellar ataxia: an update

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.

Keywords: Molecular diagnosis; Next-generation sequencing; Spinocerebellar ataxia.

Fig. 1

Mechanism of polyglutamine protein expansion repeats. a Normal translation of polyglutamine repeat within normal repeat range, producing normal protein transcript and protein folding. b Pathogenic polyglutamine expansion repeat length leads to translation of expanded abnormal PolyQ repeat, which leads to protein misfolding. Misfolded polyQ proteins form aggregates which lead to various cellular process dysfunctions, leading to cell toxicity and degeneration. PolyQ polyglutamine proteins

Fig. 2

Harding’s classification of Spinocerebellar Ataxia, detailing the classification of SCA based on symptom presentation and the associated SCAs with that classification

Fig. 3

Flowchart of diagnosis pathway based on either positive or negative result of each diagnostic test. −ve—negative

Fig. 4

Mechanism of RNA foci formation and effects. a Pathogenic SCA intronic and exonic expansion repeats; b transcription of expanded repeat into expanded mRNA/pre-RNA; c binding of regulatory binding proteins (RBP) to abnormal mRNA transcript; d RBP protein sequestration and abnormal transcript aggregation; e effects of RBP sequestration on cellular processes. RBP regulatory binding proteins, RAN repeat-associated non-ATG