Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance.

中文翻译：

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亨廷顿舞蹈病的发病机理是通过Alfy / Wdfy3和选择性巨噬细胞自噬进行的。

尽管是由HTT基因的已知编码突变引起的常染色体显性遗传疾病，但具有类似三核苷酸重复突变的亨廷顿氏病（HD）患者的发病年龄可能相差数十年。一个可能的促成因素是患者的遗传异质性，可能改变他们对疾病的脆弱性。我们报告，尽管自噬衔接蛋白Alfy / Wdfy3的杂合耗竭在对照小鼠中没有影响，但它显着加速了HD发病机理的发病年龄和进展。成年大脑中需要Alfy来清除蛋白质沉积物的自噬依赖性，其在小鼠和源自患者成纤维细胞的神经元中的耗竭加速了这种成年性神经退行性疾病共有的病理学标志的异常积累。