Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration

Guohua Lv, Nicole M. Sayles, Yun Huang, Chiara Mancinelli, Kevin McAvoy, Neil A. Shneider, Giovanni Manfredi, Hibiki Kawamata () and David Eliezer ()
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Guohua Lv: Weill Cornell Medicine
Nicole M. Sayles: Weill Cornell Medicine
Yun Huang: Weill Cornell Medicine
Chiara Mancinelli: Weill Cornell Medicine
Kevin McAvoy: Weill Cornell Medicine
Neil A. Shneider: Columbia University Irving Medical Center
Giovanni Manfredi: Weill Cornell Medicine
Hibiki Kawamata: Weill Cornell Medicine
David Eliezer: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62149-3

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