German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Tübingen 72076, Germany; Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Cell Rep. 2018 Jun 5;23(10):2976-2988. doi: 10.1016/j.celrep.2018.05.009.
While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases.
虽然线粒体功能障碍在帕金森病（PD）中被认为是关键，但一个核心问题仍然是线粒体是否是真正的疾病驱动因素，以及增强线粒体生物发生和功能是否能改善病理学。我们使用源自患者的诱导多能干细胞和与 GBA 相关的 PD（GBA-PD）的果蝇模型来解决这些问题，GBA-PD 是最常见的 PD 遗传风险因素。患者神经元表现出应激反应、线粒体死亡和 NAD+代谢变化。已经提出 NAD+前体可以改善与年龄相关的代谢下降和疾病。我们报告说，通过 NAD+前体烟酰胺核糖苷（NR）增加 NAD+可以显著改善患者神经元的线粒体功能。人类神经元需要烟酰胺磷酸核糖转移酶（NAMPT）来维持 NAD+池，并利用 NRK1 从 NAD+前体合成 NAD+。值得注意的是，NR 可以预防 GBA-PD 果蝇模型中与年龄相关的多巴胺能神经元丢失和运动功能下降。我们的研究结果表明，NR 是 PD 和其他神经退行性疾病神经保护的可行临床途径。
