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.

中文翻译：

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ataxin-3去泛素酶功能及其在马查多-约瑟夫病等疾病发病机制中的作用

马查多-约瑟夫病 (MJD) 是一种破坏性且无法治愈的神经退行性疾病，其特征是进行性共济失调、说话和吞咽困难。因此，受影响的人最终会依赖轮椅，需要持续护理，并面临预期寿命缩短的问题。MJD 的单基因原因是 ATXN3 基因内三核苷酸 (CAG) 重复区域的扩展，从而导致所得 ataxin-3 蛋白内多聚谷氨酰胺 (polyQ) 的扩展。虽然已经明确 ataxin-3 蛋白作为去泛素化 (DUB) 酶发挥作用，因此在蛋白质稳态中发挥着重要作用，但关于 ataxin-3 中的 PolyQ 扩增对其 DUB 功能的影响，仍有几个未解答的问题。在此，我们回顾了有关 ataxin-3 的 DUB 功能、其 DUB 靶标以及有关 polyQ 扩展对 ataxin-3 的 DUB 功能的影响的现有文献。我们还考虑了 ataxin-3 的 DUB 功能的潜在神经保护作用，以及 ataxin-3 作为 DUB 酶和基因转录调节因子的交叉作用。Ataxin-3 是 MJD 的主要致病蛋白，似乎也与癌症有关。由于异常去泛素化与神经退行性变和癌症有关，因此全面了解 ataxin-3 的 DUB 功能对于阐明这些复杂情况下的潜在治疗靶点非常重要。在这篇综述中，我们的目标是巩固 ataxin-3 作为 DUB 的知识，并揭示未来研究领域，以帮助靶向 ataxin-3 的 DUB 功能来治疗 MJD 和其他疾病。