title: Enhancing NAD+salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease.
abstract: Familial forms of Parkinson's disease (PD) caused by mutations inPINK1are linked to mitochondrial impairment. Defective mitochondria are also found inDrosophilamodels of PD withpink1mutations. The co-enzyme nicotinamide adenine dinucleotide (NAD+) is essential for both generating energy in mitochondria and nuclear DNA repair through NAD+-consuming poly(ADP-ribose) polymerases (PARPs). We found alterations in NAD+salvage metabolism inDrosophila pink1mutants and showed that a diet supplemented with the NAD+precursor nicotinamide rescued mitochondrial defects and protected neurons from degeneration. Additionally, a mutation ofParpimproved mitochondrial function and was neuroprotective in thepink1mutants. We conclude that enhancing the availability of NAD+by either the use of a diet supplemented with NAD+precursors or the inhibition of NAD+-dependent enzymes, such as PARPs, which compete with mitochondria for NAD+, is a viable approach to preventing neurotoxicity associated with mitochondrial defects.
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Susann
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK martins.lmiguel@gmail.com shyl1@le.ac.uk.
authors.forename: Samantha H Y
authors.initials: SH
authors.lastname: Loh
authors.affiliation: MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK martins.lmiguel@gmail.com shyl1@le.ac.uk.
authors.forename: L Miguel
authors.identifier: http://orcid.org/0000-0002-3019-4809
authors.initials: LM
authors.lastname: Martins
keywords: Drosophila; Mitochondria; NAD+; NAM; Niacin; Nucleotide metabolism; PARP; PINK1; Parkinson's disease