Lv Guohua, Sayles Nicole M, Huang Yun, Mancinelli Chiara, McAvoy Kevin, Shneider Neil A, Manfredi Giovanni, Kawamata Hibiki, Eliezer David
Department of Biochemistry, Weill Cornell Medicine, 1300 York Avenue, New York, NY, USA.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Nat Commun. 2025 Aug 2;16(1):7121. doi: 10.1038/s41467-025-62149-3.
Mitochondrial proteins CHCHD10 and CHCHD2 are mutated in rare cases of heritable FTD, ALS and PD and aggregate in tissues affected by these diseases. Here, we show that both proteins form amyloid fibrils and report cryo-EM structures of fibrils formed from their disordered N-terminal domains. The ordered cores of these fibrils are comprised of a region highly conserved between the two proteins, and a subset of the CHCHD10 and CHCHD2 fibril structures share structural similarities and appear compatible with sequence variations in this region. In contrast, disease-associated mutations p.S59L in CHCHD10 and p.T61I in CHCHD2, situated within the ordered cores of these fibrils, cannot be accommodated by the wildtype structures and promote different protofilament folds and fibril structures. These results link CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration and further suggest that fibril formation by the WT proteins could also be involved in disease etiology.
线粒体蛋白CHCHD10和CHCHD2在罕见的遗传性额颞叶痴呆（FTD）、肌萎缩侧索硬化症（ALS）和帕金森病（PD）病例中发生突变，并在受这些疾病影响的组织中聚集。在这里，我们表明这两种蛋白都能形成淀粉样纤维，并报告了由它们无序的N端结构域形成的纤维的冷冻电镜结构。这些纤维的有序核心由两种蛋白之间高度保守的区域组成，并且CHCHD10和CHCHD2纤维结构的一个子集具有结构相似性，并且似乎与该区域的序列变异兼容。相比之下，位于这些纤维有序核心内的CHCHD10中的疾病相关突变p.S59L和CHCHD2中的p.T61I不能被野生型结构容纳，并促进不同的原丝折叠和纤维结构。这些结果将CHCHD10和CHCHD2淀粉样纤维与神经退行性变联系起来，并进一步表明野生型蛋白形成纤维也可能参与疾病病因。
