CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.
CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Singapore, SG · Author affiliation
Department of Research, National Neuroscience Institute, Singapore, Singapore.Location evidence
Hong Kong, HK · Author affiliation
School of Optometry, Department of Applied Biology and Chemical Technology, Research Centre for SHARP Vision (RCSV), Hong Kong Polytechnic University, Hong Kong, China.Location evidence
Guangzhou, CN · Author affiliation
Department of Anaesthesiology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Cener, Guangzhou, China.Location evidence
CN · Author affiliation · country only
Faculty of Health Sciences, Ministry of Education Frontiers Science Centre for Precision Oncology, University of Macau, Macau, China.Location evidence
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Original abstract
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 CHCHD2, and also in human iPSC-derived CHCHD2-/- or CHCHD2T61I 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.Abbreviations: AA: amino acid; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG8: mammalian Atg8-family protein; ATG13: autophagy related 13; bafA1: bafilomycin A1; C1QBP/p32/gC1qR/HABP1: complement component 1, q subcomponent binding protein; CHCHD2/MNRR1/MIX17B: coiled-coil-helix-coiled-coil-helix domain containing 2; CHCHD10/MIX17A: coiled-coil-helix-coiled-coil-helix domain containing 10; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CRISPR: clustered regularly interspaced short palindromic repeats; CQ, chloroquine; DA: dopaminergic; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; RB1CC1/FIP200: RB1 inducible coiled-coil 1; FTD: frontotemporal dementia; GABARAP: gamma-aminobutyric acid receptorbassociated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; hESC: human embryonic stem cells; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LIR: LC3-interacting region; PD: Parkinson disease; SQSTM1/p62: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein; TH: tyrosine hydroxylase; TMR, tetramethylrhodamine; WT: wild type; UB: ubiquitin; ULK1: unc-51 like kinase 1.