Source: europepmc · Origin: SG · Wei Z, Zhang M, Tang W, Singh BK, Zhiwei Z, Lei Z, Goh Kim Wee J, Tan Rui En F, Jingxiu H, Qiaoyang S, Bin X, Priyanka G · Autophagy · 2026-05-25
URL: https://pubmed.ncbi.nlm.nih.gov/42183628/
AI rationale (5/5, tier: emerging): Directly characterizes macroautophagy mechanism (GABARAP/ATG8 interaction) in neurodegeneration; mechanistic study linking genetic mutations to autophagy flux.
Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of <i>CHCHD2</i>, and also in human iPSC-derived <i>CHCHD2</i><sup>-/-</sup> or <i>CHCHD2</i><sup><i>T61I</i></sup> dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.