Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Abstract

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.

CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

“…Studies reported that knockdown of both mATXN3 and wtATXN3 alleles using RNAi and ASO, were a doubleedged sword to SCA3/MJD models. Therefore, strategies aimed at selective silencing mutant alleles are developing rapidly [10,15,18,19,52]. In this study, we delivered paired sgRNA/Cas9n and donor DNA as modi cation templates to achieve HR repair, which was consistent with previous HD studies [24,25,53].…”

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

“…The normal polyQ tract in SCA proteins is generally polymorphic in length, while beyond an apparent threshold the diseases become fully penetrant. Depending on the SCA, the pathogenic properties of the mutated protein can appear with an expansion ranging from 20 to several hundreds of glutamines (Buijsen et al, 2019). PolyQ SCAs are generally adult onset disorders and progress over 10-20 years before leading to death of patients (Klockgether, 2011).…”

Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency

“…We focused on this apparent dysregulation of protein homeostasis in A-T cells because many of the more common neurodegenerative diseases in the human population are associated with aggregation of specific polypeptides in the brain, in some cases with clear causative links between the aggregation and neurotoxicity, and diverse model systems have confirmed these relationships (Bourdenx et al, 2017;Currais et al, 2017;Gidalevitz et al, 2006;Groh et al, 2017; Kikis et al, 2010;Ross and Poirier, 2004). In addition, several of the SCA ataxias, while associated with diverse genetic mutations, generate aggregation-prone mutant proteins that cause cerebellum-specific neurodegeneration similar to that observed in A-T (Buijsen et al, 2019;Klockgether et al, 2019).…”