From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

Abstract

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.

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

“…7a-b). Studies showed that abnormal changes in intracellular ROS and Ca 2+ levels were correlated with various neurodegenerative diseases [47][48][49][50]. In the present study, the ROS and intracellular Ca 2+ levels were signi cantly higher in SCA3/MJD-NCs compared with Ctr1-NCs, while obviously decreased in the corrected SCA3/MJD-NCs ( Fig.…”

Repeat Expansion Disorders: Mechanisms and Therapeutics

“…SCA3 Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is caused by a polyQ expansion in the ataxin-3 protein [18]. Ataxin-3 is a ubiquitin ligase and Da Silva et al present a unifying molecular mechanism for disease pathogenesis focusing on the disruption of protein homeostasis [19]. This molecular mechanism is common to all polyQ diseases and key networks are likely shared between the diseases.…”

RAN translation of the expanded CAG repeats in the SCA3 disease context

“…Thus, we assume that the amount of polyQ proteins observed for the cells expressing the AUG-78/32-117CAG construct under ER and oxidative stress was the result of reduced canonical translation and increased RAN translation. Altogether, as age-dependent accumulation of misfolded mutant ataxin-3 can lead to activation of various cellular stress pathways, it is very likely that the amount of RAN proteins increase over time and, as a consequence, the pathogenesis of SCA3 is accelerated [1][2][3][4].…”

“…SCA3 is caused by an expanded stretch of CAG repeats in exon 10 of the ATXN3 gene, which encodes the deubiquitinating enzyme ataxin-3. These repeat tracts range in ATXN3 from 12 to 44 triplets in healthy individuals and from 56 to 87 in SCA3 patients [1][2][3][4]. Until recently, it was believed that the expanded CAG repeats in SCA3 exerted their pathogenic effects at only the protein level.…”

“…Until recently, it was believed that the expanded CAG repeats in SCA3 exerted their pathogenic effects at only the protein level. The presence of an abnormally long tract of glutamine in the C-terminal region of ataxin-3 leads to a toxic gain-of-function of the protein, which manifests mainly as characteristic neuronal cytoplasmic and nuclear aggregates [1][2][3][4]. However, there is also mounting evidence to suggest that mutant transcripts contribute to the pathogenesis of SCA3 via an RNA gain-of-function mechanism [1,5,6].…”