Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease

Cell Death Dis. 2016 Mar 31;7(3):e2166. doi: 10.1038/cddis.2016.72.

Abstract

The co-enzyme nicotinamide adenine dinucleotide (NAD(+)) is an essential co-factor for cellular energy generation in mitochondria as well as for DNA repair mechanisms in the cell nucleus involving NAD(+)-consuming poly (ADP-ribose) polymerases (PARPs). Mitochondrial function is compromised in animal models of Parkinson's disease (PD) associated with PARKIN mutations. Here, we uncovered alterations in NAD(+) salvage metabolism in Drosophila parkin mutants. We show that a dietary supplementation with the NAD(+) precursor nicotinamide rescues mitochondrial function and is neuroprotective. Further, by mutating Parp in parkin mutants, we show that this increases levels of NAD(+) and its salvage metabolites. This also rescues mitochondrial function and suppresses dopaminergic neurodegeneration. We conclude that strategies to enhance NAD(+) levels by administration of dietary precursors or the inhibition of NAD(+)-dependent enzymes, such as PARP, that compete with mitochondria for NAD(+) could be used to delay neuronal death associated with mitochondrial dysfunction.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / metabolism
  • Dietary Supplements
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Genotype
  • Longevity
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mutagenesis
  • NAD / metabolism
  • Niacinamide / pharmacology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Drosophila Proteins
  • NAD
  • Niacinamide
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Poly(ADP-ribose) Polymerases