Mission Team, Huntington's Disease Society of America, New York, NY, USA.
Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, NY, USA.
Autophagy. 2020 May;16(5):967-968. doi: 10.1080/15548627.2020.1739448. Epub 2020 Mar 13.
The role protein aggregates play in the pathogenesis of neurodegenerative diseases has been a question since their initial observation. In this autophagic punctum, we discuss our recent findings of how the selectivity scaffold/adaptor WDFY3/Alfy is required for the turnover of aggregated mutant HTT (huntingtin; mHTT) in the adult brain, and how it confers resistance to Huntington disease (HD)-like symptoms. Depletion of WDFY3 in a mouse model of HD accelerates mHTT accumulation, and this is accompanied by an accelerated onset of motoric and neuropathological phenotypes, indicating that WDFY3 levels and the rate of aggregate accumulation can modify disease pathogenesis. Given that the accelerated accumulation is also recapitulated in medium spiny neurons created via direct conversion from human HD fibroblasts, we propose that WDFY3 is a genetic modifier of HD and suggest that it may also influence aging and the pathogenesis of other neurological disorders.
自最初观察到蛋白聚集在神经退行性疾病发病机制中的作用以来，这一直是一个问题。在这个自噬小点中，我们讨论了我们最近的发现，即选择性支架/衔接蛋白 WDFY3/Alfy 如何在成年大脑中被需要来进行聚集突变 HTT（亨廷顿氏病；mHTT）的周转，以及它如何赋予对亨廷顿病（HD）样症状的抗性。在 HD 的小鼠模型中耗尽 WDFY3 会加速 mHTT 的积累，并且伴随着运动和神经病理学表型的加速发作，这表明 WDFY3 水平和聚集物积累的速度可以改变疾病的发病机制。鉴于这种加速积累也可以在通过直接从人类 HD 成纤维细胞转化而来的中间棘神经元中重现，我们提出 WDFY3 是 HD 的遗传修饰因子，并表明它也可能影响衰老和其他神经疾病的发病机制。
