Lv Guohua, Sayles Nicole M, Huang Yun, Mancinelli Chiara D, McAvoy Kevin, Shneider Neil A, Manfredi Giovanni, Kawamata Hibiki, Eliezer David
Department of Biochemistry, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, United States.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 E 61 Street, New York, NY 10065, United States.
bioRxiv. 2024 Jul 22:2024.07.18.604174. doi: 10.1101/2024.07.18.604174.
CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.
CHCHD10在罕见的额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）病例中发生突变，并在疾病的小鼠模型中聚集。在此我们表明，CHCHD10无序的N端结构域形成淀粉样原纤维，并报告了它们的冷冻电镜结构。野生型（WT）原纤维结构无法容纳与疾病相关的突变，而CHCHD10和CHCHD2之间的序列差异是可耐受的，这解释了这两种蛋白质的共聚集现象，并将CHCHD10和CHCHD2淀粉样原纤维与神经退行性变联系起来。
