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Abstract：
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.
摘要：
Machado-Joseph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,受影响的个体最终变得依赖轮椅，需要不断的照顾，并面临寿命缩短的问题。MJD的单基因原因是ATXN3基因内三核苷酸（CAG）重复区的扩增，这导致在所得的共济失调蛋白-3蛋白内聚谷氨酰胺(polyQ)扩增。虽然已经确定ataxin-3蛋白作为去泛素化（DUB）酶起作用，因此严重参与蛋白质停滞，关于ataxin-3中polyQ扩增对其DUB功能的影响,仍有几个未解决的问题.在这里，我们回顾了当前围绕ataxin-3的DUB功能的文献，它的DUB目标，以及关于polyQ扩展对ataxin-3的DUB功能的影响的已知信息。我们还考虑了共济失调蛋白-3的DUB功能的潜在神经保护作用，以及共济失调蛋白-3作为DUB酶和基因转录调节因子的作用的交叉点。Ataxin-3是MJD中的主要致病蛋白,并且似乎也与癌症有关。由于异常的去泛素化与神经变性和癌症有关，全面了解ataxin-3的DUB功能对于阐明这些复杂条件下的潜在治疗靶点非常重要.在这次审查中,我们的目标是巩固有关ataxin-3作为DUB的知识,并揭示未来研究领域,以帮助治疗靶向ataxin-3的DUB功能治疗MJD和其他疾病.
