Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
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DOI：
10.1016/j.neuron.2019.12.003
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发表时间：
2020-03-04
期刊：
影响因子：
16.2
通讯作者：
Yamamoto, Ai
中科院分区：
文献类型：
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作者：
Fox, Leora M.;Kim, Kiryung;Yamamoto, Ai
尽管亨廷顿病(HD)是由HTT基因已知的编码突变引起的常染色体显性遗传病，但具有类似三核苷酸重复突变的亨廷顿病患者的发病年龄可能几十年不等。一个可能的因素是患者的基因异质性，这可能会改变他们对疾病的易感性。我们报道，尽管自噬适配蛋白Alfy/Wdfy3杂合性缺失在对照组小鼠中没有后果，但它显著加速了HD发病的年龄和进展。在成人大脑中，ALFY是依赖自噬清除蛋白质沉积所必需的，它在小鼠和来自患者成纤维细胞的神经元中的枯竭加速了这种在成人起病的神经退行性疾病中共有的病理特征的异常积累。这些发现表明，选择性地损害消除聚集蛋白的能力是致病的驱动因素，选择性地消除聚集可能增强抗病能力。
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.