Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
J Neurochem. 2019 Jan;148(1):8-28. doi: 10.1111/jnc.14541. Epub 2018 Oct 5.
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.
马查多-约瑟夫病（MJD），又称脊髓小脑共济失调 3 型（SCA3），是一种无法治愈的疾病，被广泛认为是世界上最常见的脊髓小脑共济失调形式。MJD/SCA3 是由 ATXN3 基因突变引起的，但这种简单的单基因病因与目前公认的导致神经元功能障碍和死亡的致病机制的复杂性形成对比。异常扩增的蛋白产物——ataxin-3——已知会聚集并产生毒性物质，破坏包括自噬、蛋白稳态、转录、线粒体功能和信号转导在内的多个细胞系统。多年来，针对潜在治疗方法的研究经常致力于开发针对细胞发病机制不同阶段的疾病的策略。沉默致病蛋白、阻止聚集、抑制毒性蛋白水解加工以及对抗受影响的细胞系统功能障碍，在细胞和动物模型研究中产生了有希望的改善结果。目前的综述分析了专门用于研究 MJD/SCA3 发病机制和探索可能的治疗策略的现有研究，主要侧重于基于疾病的分子和细胞机制的基因治疗和药理学方法。
