Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3

Blount, Jessica R.; Patel, Nikhil C.; Libohova, Kozeta; Harris, Autumn L.; Tsou, Wei-Ling; Sujkowski, Alyson; Todi, Sokol V.

doi:10.1016/j.jns.2023.120828

Cited by 1 publication

(1 citation statement)

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“…The observation of minimal intranuclear inclusions in flies co-expressing polyQ-expanded and wild-type ataxin-3 [ 121 ] indicates that perhaps ataxin-3 is protective by suppressing the formation of inclusions rather than altering ataxin-3 protein levels, and ataxin-3's DUB role may be central to this. Consistent with these findings, a recent study reported that polyQ-expanded ataxin-3 with the K117 residue mutated to prevent ubiquitination at the site, is more toxic than polyQ-expanded ataxin-3 with an intact K117 residue in Drosophila , further suggesting that ubiquitination at K117 is protective in MJD [ 171 ].…”

Section: Does the Dub Function Of Ataxin-3 Have A Neuroprotective Role?mentioning

confidence: 55%

The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases

Potapenko,

Davidson,

Lee

et al. 2024

Biochemical Journal

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Machado-Joseph disease (MJD) is a devastating and incurable neurodegenerative disease characterised by progressive ataxia, difficulty speaking and swallowing. Consequently, affected individuals ultimately become wheelchair dependent, require constant care, and face a shortened life expectancy. The monogenic cause of MJD is expansion of a trinucleotide (CAG) repeat region within the ATXN3 gene, which results in polyglutamine (polyQ) expansion within the resultant ataxin-3 protein. While it is well established that the ataxin-3 protein functions as a deubiquitinating (DUB) enzyme and is therefore critically involved in proteostasis, several unanswered questions remain regarding the impact of polyQ expansion in ataxin-3 on its DUB function. Here we review the current literature surrounding ataxin-3's DUB function, its DUB targets, and what is known regarding the impact of polyQ expansion on ataxin-3's DUB function. We also consider the potential neuroprotective effects of ataxin-3's DUB function, and the intersection of ataxin-3's role as a DUB enzyme and regulator of gene transcription. Ataxin-3 is the principal pathogenic protein in MJD and also appears to be involved in cancer. As aberrant deubiquitination has been linked to both neurodegeneration and cancer, a comprehensive understanding of ataxin-3's DUB function is important for elucidating potential therapeutic targets in these complex conditions. In this review, we aim to consolidate knowledge of ataxin-3 as a DUB and unveil areas for future research to aid therapeutic targeting of ataxin-3's DUB function for the treatment of MJD and other diseases.

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Section: Does the Dub Function Of Ataxin-3 Have A Neuroprotective Role?mentioning

confidence: 55%

The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases

Potapenko,

Davidson,

Lee

et al. 2024

Biochemical Journal

View full text Add to dashboard Cite

show abstract

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3

Cited by 1 publication

References 49 publications

The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases

The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases

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