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Cell Rep. 2018 Jun 5;23(10):2976-2988. doi: 10.1016/j.celrep.2018.05.009.

The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease.

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Tübingen 72076, Germany; Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
2
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
3
Department of Neuroanatomy, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg 79104, Germany.
4
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
5
Emmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg 79104, Germany.
6
German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Tübingen 72076, Germany; Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany. Electronic address: michela.deleidi@dzne.de.

Abstract

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.

KEYWORDS:

GBA; NAD+; Parkinson’s disease; induced pluripotent stem cells; lysosomal storage diseases; mitochondria; neurodegeneration

PMID:
29874584
DOI:
10.1016/j.celrep.2018.05.009
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