Croce Katherine R, Ng Christopher, Pankiv Serihy, Albarran Eddy, Langfelder Peter, Ramos de Jesus Ana, Duncan Glenn M, Wang Nan, Basile Anna, McHugh Caitlin, Litt Nicole A, Li Alina, Friedman Sophia, Cortes Etty P, Zody Michael C, Yang X William, Ding Jun B, Vonsattel Jean Paul G, Simonsen Anne, Housman David E, Wexler Nancy S, Yamamoto Ai
Doctoral Program in Pathobiology and Mechanism of Disease, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Neuron. 2025 Sep 12. doi: 10.1016/j.neuron.2025.08.018.
The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases expression of the protein autophagy-linked Fab1, YOTB, Vac1, and EEA1 (FYVE) protein (Alfy), an autophagy adaptor protein for the clearance of aggregated proteins, whose ectopic overexpression is sufficient to capture the neuroprotective effects of the variant. Increasing Alfy expression protects not only against HD but also against the toxicity due to phospho-α-synuclein and AT8-positive accumulation. By combining human and mouse genetics, we have uncovered a pathway that protects against multiple proteinopathies, revealing a much-sought-after, shared therapeutic target across a broad range of neurodegenerative diseases.
疾病修饰因子的研究是识别与疾病相关的病理机制的有力方法。利用亨廷顿舞蹈症（HD）强大的遗传特征，我们在WDFY3中鉴定出一种罕见的单核苷酸多态性（SNP），其与发病年龄延迟长达23年有关。值得注意的是，将直系同源SNP导入小鼠可重现这种神经保护作用，在两种HD模型中显著延迟神经病理学和行为功能障碍。该SNP增加了自噬相关的Fab1、YOTB、Vac1和EEA1（FYVE）蛋白（Alfy）的表达，Alfy是一种用于清除聚集蛋白的自噬衔接蛋白，其异位过表达足以捕捉该变体的神经保护作用。增加Alfy表达不仅能预防HD，还能预防磷酸化α-突触核蛋白和AT8阳性积累所致的毒性。通过结合人类和小鼠遗传学，我们发现了一条预防多种蛋白病的途径，揭示了一个在广泛的神经退行性疾病中备受追捧的共同治疗靶点。
