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.

自从最初的观察以来，蛋白质聚集体在神经退行性疾病的发病机理中的作用一直是一个问题。在这种自噬性泪点中，我们讨论了我们最近的发现，即成年大脑中聚集突变体HTT（亨廷顿； mHTT）的转换需要选择性支架/衔接子WDFY3 / Alfy，以及它如何赋予对亨廷顿病（HD）的抵抗力症状。HD小鼠模型中WDFY3的耗竭加速了mHTT的积累，并且伴随着运动和神经病理学表型的加速发作，表明WDFY3的水平和聚集体的积累速率可以改变疾病的发病机理。假设加速的积累在通过人类高清成纤维细胞直接转化产生的中等棘突神经元中也有概括，