Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
Centre for Biomedical Research, University of Algarve, Faro, Portugal.
Adv Exp Med Biol. 2018;1049:349-367. doi: 10.1007/978-3-319-71779-1_18.
Machado-Joseph disease (MJD) is a dominantly inherited disorder originally described in people of Portuguese descent, and associated with the expansion of a CAG tract in the coding region of the causative gene MJD1/ATX3. The CAG repeats range from 10 to 51 in the normal population and from 55 to 87 in SCA3/MJD patients. MJD1 encodes ataxin-3, a protein whose physiological function has been linked to ubiquitin-mediated proteolysis. Despite the identification of the causative mutation, the pathogenic process leading to the neurodegeneration observed in the disease is not yet completely understood. In the past years, several studies identified different molecular mechanisms and cellular pathways as being impaired or deregulated in MJD. Autophagy, proteolysis or post-translational modifications, among other processes, were implicated in MJD pathogenesis. From these studies it was possible to identify new targets for therapeutic intervention, which in some cases proved successful in models of disease.
马查多-约瑟夫病（MJD）是一种显性遗传疾病，最初在葡萄牙裔人群中描述，与致病基因 MJD1/ATX3 编码区 CAG 重复序列的扩展有关。在正常人群中，CAG 重复次数为 10 至 51，在 SCA3/MJD 患者中为 55 至 87。MJD1 编码ataxin-3，一种与其生理功能相关的蛋白与泛素介导的蛋白水解有关。尽管已经确定了致病突变，但导致疾病中观察到的神经退行性变的致病过程尚不完全清楚。在过去的几年中，几项研究确定了不同的分子机制和细胞途径在 MJD 中受到损害或失调。自噬、蛋白水解或翻译后修饰等过程都与 MJD 的发病机制有关。从这些研究中可以确定新的治疗干预靶点，在某些情况下，这些靶点在疾病模型中被证明是成功的。
