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

Susann Lehmann,Samantha H Y Loh,L Miguel Martins

doi:10.1242/bio.022186

Susann Lehmann, Samantha H Y Loh + Show 1 more

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https://doi.org/10.1242/bio.022186

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Journal: Biology open	Publication Date: Jan 1, 2016
Citations: 73	License type: CC BY 3.0

Affiliation: MRC Toxicology Unit

Abstract

ABSTRACTFamilial 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.

Highlights

Parkinson’s disease (PD) is an age-associated neurodegenerative disorder characterised by the specific loss of dopaminergic neurons in the substantia nigra pars compacta of the brain
We demonstrated that a diet supplemented with an NAD+ precursor vitamin, nicotinamide (NAM), and the genetic suppression of Parp, a NAD+-consuming enzyme, improves mitochondrial function and prevents neurodegeneration in pink1 mutant flies
An NAD+-supplemented diet suppresses both mitochondrial defects and neurodegeneration in pink1 mutant flies NAD+ metabolism plays a crucial role in PD pathogenesis in a number of PD-associated disease models that present with mitochondrial defects (Delgado-Camprubi et al, 2016; Lehmann et al, 2016)

Summary

Introduction

Parkinson’s disease (PD) is an age-associated neurodegenerative disorder characterised by the specific loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Mitophagy involves accumulation of the kinase PINK1 in the outer mitochondrial membrane of defective mitochondria, where it cooperates with the E3 ligase Parkin and FBXO7, an E3 ligase adaptor, to promote their autophagic degradation (reviewed in Celardo et al, 2014). Mutations in PINK1, PARKIN and FBXO7 have been identified in families with autosomal recessive earlyonset PD (Di Fonzo et al, 2009; Kitada et al, 1998; Valente et al, 2004). This suggests that defects in mitophagy might have a MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK

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