Metabolic defects cause hyperactive mitochondria and Parkinson’s disease-like traits

Metabolic dysfunction is a facet of many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood 1 . 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) 2 . Knockdown of C. elegans bcat-1 recapitulates PD-like features, including progressive motor deficits and neurodegeneration with age 2 . 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) worms 3 . 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.