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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Drosophila melanogaster / physiology*
  • Endoplasmic Reticulum Stress
  • Glucosylceramidase / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics
  • Motor Activity
  • NAD / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Parkinson Disease / pathology*
  • Parkinson Disease / physiopathology
  • Unfolded Protein Response

Substances

  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Glucosylceramidase