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...

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Bibliographic Details
Published in:	Nature cell biology Vol. 16; no. 2; pp. 157 - 166
Main Authors:	Tufi, Roberta, Gandhi, Sonia, de Castro, Inês P., Lehmann, Susann, Angelova, Plamena R., Dinsdale, David, Deas, Emma, Plun-Favreau, Hélène, Nicotera, Pierluigi, Abramov, Andrey Y., Willis, Anne E., Mallucci, Giovanna R., Loh, Samantha H. Y., Martins, L. Miguel
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-02-2014 Nature Publishing Group
Subjects:	13/89 14/1 14/10 14/19 14/28 14/5 38/39 45 45/61 631/136/334/1582 631/136/368 631/80/642/333 64/24 Animals Biosynthesis Cancer Research Cell Biology Complications and side effects Developmental Biology Disease Disease Models, Animal DNA, Mitochondrial - biosynthesis Drosophila melanogaster Drosophila Proteins - genetics Drosophila Proteins - physiology Gene mutations Health aspects Homocysteine Insects Kinases Life Sciences Metabolism Mitochondria - physiology Mitochondrial diseases Mitochondrial DNA Mutants Mutation Neurodegeneration Nucleotides - metabolism Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson Disease - physiopathology Parkinson's disease Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - physiology Risk factors Stem Cells United Kingdom United Kingdom > UK
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Summary:	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. Mutations in PINK1 cause early-onset Parkinson’s disease. Martins and colleagues find that the expression levels of genes involved in nucleotide metabolism are upregulated in a Drosophila pink1 mutant, and that this affects neuronal mitochondrial DNA synthesis. They find that enhancing nucleotide synthesis through genetics or pharmacological approaches rescues mitochondrial defects associated with PINK1 mutations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS: A.Y.A., G.R.M., L.M.M., R.T. and S.H.Y.L. conceived and designed the experiments. A.Y.A., D.D., I.P.d.C., L.M.M., P.R.A., R.T., S.G., S.L. and S.H.Y.L. performed the experiments and analysed the data. R.T. did most of the experimental work and analysis. E.D. contributed materials. A.E.W., H.P-F. and P.N. provided experimental and conceptual advice. G.R.M., L.M.M., R.T., S.G. and S.H.Y.L wrote the paper. S.H.Y.L. and L.M.M. contributed equally as joint last authors.
ISSN:	1465-7392 1476-4679
DOI:	10.1038/ncb2901