期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 42, 页码 26438-26447出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2009838117
关键词
Parkinson's disease; metformin; mitochondria; branched-chain amino acid metabolism; Caenorhabditis elegans
资金
- C. elegans Genetics Center for strains [P40 OD010440]
- Ruth L. Kirschstein National Research Service Award [NIA F32AG062036]
- NIH [NIEHS U2CES030163, R01 ES023839, NIGMS 5DP1GM119167]
- Glenn Foundation for Medical Research [CNV1001899]
Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or mitochondrial hyperactivity, is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post-disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.
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