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. Lv et al. discover that

Lv et al. discover that homologous disordered regions of proteins linked to ALS/FTD and Parkinson’s, CHCHD10 and CHCHD2, form amyloid fibrils in vitro and that the structures of these fibrils are cons...

In a groundbreaking advancement that offers new insights into the molecular origins of devastating neurodegenerative diseases, researchers have unveiled the structural underpinnings of amyloid fibrils formed by the proteins CHCHD10 and CHCHD2. These discoveries not only shed light on the intricate mechanisms by which these proteins contribute to neurodegeneration but also open promising avenues for therapeutic interventions targeting conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

The CHCH domains of D10 and D2 are predicted to be folded, but the structural properties of the low complexity domains of both proteins, which include putative mitochondrial targeting sequences (MTS) and central α-helix domains (Fig. 1a), have been explored...

Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present w...

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembra

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembra

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we s

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we s