PDF(Pubmed)
Abstract：
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson\'s disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.
摘要：
Machado-Joseph病（MJD）是由ATXN3基因中聚谷氨酰胺编码CAG重复扩增引起的常染色体显性神经退行性脊髓小脑共济失调。虽然CAG长度与发病年龄呈负相关，它只占其变异性的大约50%。尽管在确定遗传因素方面做出了更大的努力，对MJD的分子发病机制具有强大和合理影响的候选基因很少。因此,我们分析了编码帕金森病相关E3泛素连接酶parkin的PRKN基因中的错义单核苷酸多态性变异，它是MJD蛋白ataxin-3（一种去泛素酶）的良好描述的相互作用伙伴。通过对迄今为止最大的900多名MJD队列进行相关性分析，我们将V380L变体确定为相关因素，纯合携带者的发病年龄降低3岁。MJD细胞模型中的功能分析表明，parkinV380L不调节ataxin-3的可溶性或聚集体水平，但降低了两种蛋白质的相互作用。此外，ParkinV380L的存在会干扰线粒体自噬的执行-自噬清除多余或受损的线粒体-从而损害细胞活力。总之,我们将Parkin中的V380L变异体鉴定为MJD的遗传修饰体,对其分子发病机制和发病年龄有负面影响。
