Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26438-26447. doi: 10.1073/pnas.2009838117. Epub 2020 Oct 6.
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 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of 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 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 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.
代谢功能障碍发生在许多与年龄相关的神经退行性疾病中，但它在疾病发病机制中的作用仍知之甚少。我们最近发现了支链氨基酸转移酶与神经退行性运动障碍帕金森病（PD）之间的潜在因果关系。RNAi 介导的 敲低已知可再现 PD 样特征，包括进行性运动缺陷和与年龄相关的神经退行性变，但潜在机制仍不清楚。在这里，我们使用转录组学、代谢组学和成像方法表明， 敲低通过哺乳动物雷帕霉素靶蛋白（mTOR）独立机制增加神经元中线粒体呼吸并诱导氧化损伤。线粒体呼吸的增加，或“线粒体过度活跃”，是 神经毒性所必需的。此外，我们还表明，疾病发病后给予 2 型糖尿病药物二甲双胍可将线粒体呼吸降低至控制水平，并显著改善运动功能和神经元活力。总之，我们的研究结果表明，线粒体过度活跃可能是 PD 发病机制中的早期事件，而旨在降低线粒体呼吸的策略可能为 PD 治疗提供一条令人惊讶的新途径。
