Journal
CELL REPORTS
Volume 23, Issue 10, Pages 2979-U198Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.05.009
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Funding
- German Research Council (DFG) [DE 2157/2-1]
- Helmholtz Association [VH-NG-1123]
- Marie Curie Career Integration Grant [CIG304108]
- Medical Research Council [MC-A070-5PSB0]
- European Research Council [309742]
- Lipidomics Shared Resource in the South Carolina Lipidomics and Pathobiology COBRE
- MUSC Department of Biochemistry [P20 RR017677]
- National Center for Research Resources and Office of the Director of the National Institutes of Health [C06 RR018823]
- Medical University of South Carolina [P30 CA138313]
- MRC [MR/R011354/1, MC_UU_00015/6, MC_UP_1501/1] Funding Source: UKRI
- European Research Council (ERC) [309742] Funding Source: European Research Council (ERC)
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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.
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