BPS2026 – Amyloid fibril of CHCHD10 and CHCHD2 linked to neurodegeneration

Mitochondrial proteins CHCHD10 and CHCHD2 are mutated in rare cases of familial FTD, ALS, and PD and are found deposited as aggregates in these diseases. We show that both proteins form amyloid fibrils in vitro and report cryo-EM structures of fibrils formed from their disordered N-terminal domains. We also provide evidence for amyloid formation by CHCHD10 in vivo. The ordered cores of these fibrils are comprised of the most highly conserved region between the two proteins, and a subset of the CHCHD10 and CHCHD2 fibril structures share structural similarities and appear compatible with the few sequence variations in this region. In contrast, disease-associated point mutations S59L in CHCHD10 and T61I in CHCHD2, situated within the ordered cores of these fibrils, cannot be accommodated by the wild-type structures and result in different protofilament folds and fibril structures, suggesting the potential for structural disease strains. 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.