title: Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease.
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.
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Costa
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: I
authors.initials: I
authors.lastname: Celardo
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: S H Y
authors.initials: SH
authors.lastname: Loh
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D008136:Longevity; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016296:Mutagenesis; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D009243:NAD; D009536:Niacinamide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D011065:Poly(ADP-ribose) Polymerases