Abramov, AY;
Gegg, M;
Grunewald, A;
Wood, NW;
Klein, C;
Schapira, AHV;
(2011)
Bioenergetic Consequences of PINK1 Mutations in Parkinson Disease.
PLOS ONE
, 6
(10)
, Article e25622. 10.1371/journal.pone.0025622.
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Abstract
Background: Mutations of the gene for PTEN-induced kinase 1 (PINK1) are a cause of familial Parkinson's disease (PD). PINK1 protein has been localised to mitochondria and PINK1 gene knockout models exhibit abnormal mitochondrial function. The purpose of this study was to determine whether cells derived from PD patients with a range of PINK1 mutations demonstrate similar defects of mitochondrial function, whether the nature and severity of the abnormalities vary between mutations and correlate with clinical features.Methodology: We investigated mitochondrial bioenergetics in live fibroblasts from PINK1 mutation patients using single cell techniques. We found that fibroblasts from PINK1 mutation patients had significant defects of bioenergetics including reduced mitochondrial membrane potential, altered redox state, a respiratory deficiency that was determined by substrate availability, and enhanced sensitivity to calcium stimulation and associated mitochondrial permeability pore opening. There was an increase in the basal rate of free radical production in the mutant cells. The pattern and severity of abnormality varied between different mutations, and the less severe defects in these cells were associated with later age of onset of PD.Conclusions: The results provide insight into the molecular pathology of PINK1 mutations in PD and also confirm the critical role of substrate availability in determining the biochemical phenotype - thereby offering the potential for novel therapeutic strategies to circumvent these abnormalities.
| Type: | Article |
|---|---|
| Title: | Bioenergetic Consequences of PINK1 Mutations in Parkinson Disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0025622 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0025622 |
| Language: | English |
| Additional information: | © 2011 Abramov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC), and by Kattan Trust. Dr. Abramov is a Parkinson's UK Senior Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. |
| Keywords: | MITOCHONDRIAL DYSFUNCTION, PINK1/PARKIN PATHWAY, OXIDATIVE STRESS, NEURODEGENERATION, MITOPHAGY, MORPHOLOGY, MITOFUSIN, DEFECTS, CALCIUM, DNA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1329588 |
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