Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

Abstract

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an incurable disorder, widely regarded as the most common form of spinocerebellar ataxia in the world. MJD/SCA3 arises from mutation of the ATXN3 gene, but this simple monogenic cause contrasts with the complexity of the pathogenic mechanisms that are currently admitted to underlie neuronal dysfunction and death. The aberrantly expanded protein product - ataxin-3 - is known to aggregate and generate toxic species that disrupt several cell systems, including autophagy, proteostasis, transcription, mitochondrial function and signalling. Over the years, research into putative therapeutic approaches has often been devoted to the development of strategies that counteract disease at different stages of cellular pathogenesis. Silencing the pathogenic protein, blocking aggregation, inhibiting toxic proteolytic processing and counteracting dysfunctions of the cellular systems affected have yielded promising ameliorating results in studies with cellular and animal models. The current review analyses the available studies dedicated to the investigation of MJD/SCA3 pathogenesis and the exploration of possible therapeutic strategies, focusing primarily on gene therapy and pharmacological approaches rooted on the molecular and cellular mechanisms of disease.

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“…Moreover, treatment of patient-derived neuronal cultures with GSK3b inhibitors resulted in a significant reduction of pTAU aggregates [37]. ATAXIN-3 aggregates cause degeneration of cells in the hindbrain [85]. HD is a polyglutamine disease caused by CAG repeat expansion in the HTT gene [84].…”

“…Machado-Joseph disease (MJD or spinocerebellar ataxia type III) is another type of polyglutamine diseases caused by unstable CAG repeats in the ATXN3 gene, resulting in an abnormal, aggregate-prone form of ATAXIN-3. ATAXIN-3 aggregates cause degeneration of cells in the hindbrain [85]. Sheng et al [48] derived iNSCs from MJD patients, which successfully recapitulated the cellular and molecular hallmarks of the disease in vitro, such as the formation of SDS-insoluble ataxin aggregates in neuronal cultures.…”

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].…”