CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.
CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Gladstone, US · Author affiliation
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.Location evidence
San Francisco, US · Author affiliation
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.Location evidence
Berkeley, US · Author affiliation
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.Location evidence
US · Author affiliation · country only
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.Location evidence
Regina, CA · Author affiliation
Department of Biochemistry, University of Regina, Regina, Saskatchewan, Canada.Location evidence
Sydney, AU · Author affiliation
Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, University of Sydney, Sydney, Australia.Location evidence
Ben Guerir, MA · Author affiliation
Faculty of Medical Sciences, UM6P Hospitals, Mohammed VI Polytechnic University, Ben Guerir, Morocco.Location evidence
New York City, US · Author affiliation
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.Location evidence
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Original abstract
Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.