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Article (Scientific journals)
Bioenergetic consequences of PINK1 mutations in Parkinson disease.
Abramov, Andrey Yurevich; Gegg, Matthew; Grünewald, Anne et al.
2011In PLoS ONE, 6 (10), p. 25622
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Keywords :
Adult; Aged; Cells, Cultured; Energy Metabolism/genetics; Fibroblasts/pathology; Humans; Metabolism; Middle Aged; Mitochondria/genetics/pathology/physiology; Mutation/physiology; Parkinson Disease/genetics/pathology; Permeability; Phenotype; Protein Kinases/genetics
Abstract :
[en] 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.
Disciplines :
UNKNOWN KEY #A01
Author, co-author :
Abramov, Andrey Yurevich
Gegg, Matthew
Grünewald, Anne  
Wood, Nicholas William
Klein, Christine 
Schapira, Anthony Henry Vernon
External co-authors :
yes
Language :
English
Title :
Bioenergetic consequences of PINK1 mutations in Parkinson disease.
Publication date :
2011
Journal title :
PLoS ONE
ISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Volume :
6
Issue :
10
Pages :
e25622
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 05 February 2016

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