Enhancing NAD+?salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease

摘要

Familial forms of Parkinson's disease (PD) caused by mutations in?PINK1?are linked to mitochondrial impairment. Defective mitochondria are also found in?Drosophila?models of PD with?pink1?mutations. 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 in?Drosophila pink1?mutants and showed that a diet supplemented with the NAD+?precursor nicotinamide rescued mitochondrial defects and protected neurons from degeneration. Additionally, a mutation of?Parp?improved mitochondrial function and was neuroprotective in the?pink1?mutants. 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.