Toward understanding Machado–Joseph disease

Abstract

Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

“…Ataxin-3 has been associated with protein homeostasis and transcriptional regulation [180]. Ataxin-3 has ubiquitin-protease activity and up to three ubiquitin-binding motifs, being thought to directly regulate ubiquitination-dependent degradation pathways [181].…”

“…Consistently with its function in transcription, expression of mutant ataxin-3 in SCA3 transgenic mice altered the expression of several genes including those involved in the heat shock response [31]. Although both cytoplasmic and nuclear aggregates have been described in SCA3 brains [180], the nucleus is thought to be the principal site of SCA3 pathogenesis [183].…”

T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse

“…Wild-type ataxin-3 acts as a deubiquitinating enzyme and regulates the ubiquitin-proteasome pathway (Matos et al, 2011;Costa and Paulson, 2012).…”

“…Wild-type ataxin-3 contains C-terminal 10-51 glutamines, and polyglutamine tract of disease-causing mutant ataxin-3 expands to 55-87 glutamines (Kobayashi and Kakizuka, 2003;Matos et al, 2011;Costa and Paulson, 2012). The pathological basis of dominantly inherited SCA3 is believed to be polyglutamine expansion-induced toxic gain-of-function mutation of ataxin-3 (Matos et al, 2011;Costa and Paulson, 2012).…”

“…Wild-type ataxin-3 contains C-terminal 10-51 glutamines, and polyglutamine tract of disease-causing mutant ataxin-3 expands to 55-87 glutamines (Kobayashi and Kakizuka, 2003;Matos et al, 2011;Costa and Paulson, 2012). The pathological basis of dominantly inherited SCA3 is believed to be polyglutamine expansion-induced toxic gain-of-function mutation of ataxin-3 (Matos et al, 2011;Costa and Paulson, 2012). Polyglutamine-expanded ataxin-3-induced neurotoxicity is mainly observed in the cerebellum, pontine nuclei, substantia nigra and spinal cord (Kobayashi and Kakizuka, 2003;Riess et al, 2008;Matos et al, 2011;Costa and Paulson, 2012).…”