Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease.
Mutations in PINK1 cause early-onset Parkinson's disease (PD). Studies in Drosophila melanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Roberta
R
Tufi
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Sonia
S
Gandhi
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Inês P
IP
de Castro
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Susann
S
Lehmann
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Plamena R
PR
Angelova
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
David
D
Dinsdale
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Emma
E
Deas
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Hélène
H
Plun-Favreau
German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Pierluigi
P
Nicotera
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Andrey Y
AY
Abramov
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Anne E
AE
Willis
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Giovanna R
GR
Mallucci
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
Samantha H Y
SH
Loh
MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
L Miguel
LM
Martins
D000818:Animals; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D000099202:PTEN-Induced Putative Kinase
D004272:DNA, Mitochondrial; D029721:Drosophila Proteins; D009711:Nucleotides; D017346:Protein Serine-Threonine Kinases; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase