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bioRxiv · 10.1101/2020.02.20.958322

Metabolic defects cause hyperactive mitochondria and Parkinson disease-like traits

Mor, D. E.·Sohrabi, S.·Kaletsky, R.·Keyes, W.·Kalia, V.·Miller, G. W.·Murphy, C. T.
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Abstract

Metabolic dysfunction is a facet of many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood1. We recently discovered a potential causal link between the branched-chain amino acid transferase, BCAT-1, and the neurodegenerative movement disorder, Parkinsons disease (PD)2. Knockdown of C. elegans bcat-1 recapitulates PD-like features, including progressive motor deficits and neurodegeneration with age2. Using transcriptomic, metabolomic, and imaging approaches, we show that bcat-1 knockdown increases mitochondrial activity and induces oxidative damage in neurons through mTOR-independent mechanisms. We recently developed a high-throughput screening platform to identify drugs that may be repurposed for PD, and found that metformin, the leading type 2 diabetes medication, significantly improves motor function in bcat-1(RNAi) worms3. Late-in-life metformin treatment restores normal mitochondrial activity levels and protects against bcat-1-associated neurodegeneration. Our results suggest that PD may originate as a metabolic disorder, and highlight metformin as a promising new drug candidate for PD treatment.

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Mor, D. E., Sohrabi, S., Kaletsky, R., Keyes, W., Kalia, V., Miller, G. W., Murphy, C. T.. 2020-02-22. Metabolic defects cause hyperactive mitochondria and Parkinson disease-like traits. https://doi.org/10.1101/2020.02.20.958322

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