Please use this identifier to cite or link to this item:
Title: Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease
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
First Published: Feb-2014
Publisher: Nature Publishing Group
Citation: Nature Cell Biology, 2014, 16 (2), pp. 157-166
Abstract: 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.
DOI Link: 10.1038/ncb2901
ISSN: 1465-7392
eISSN: 1476-4679
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2014, Nature Publishing Group. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

Files in This Item:
File Description SizeFormat 
Tufi_NCB_2014.pdfPost-review (final submitted author manuscript)3.28 MBAdobe PDFView/Open

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.