Journal Article

Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function

De Strooper, Bart, Vanbrabant, Mieke, Mandemakers, Wim, Snellinx, An, Haddad, Dominik, Roethig, Anne, Vogt‐Weisenhorn, Daniela, Frezza, Christian, Van Coster, Rudy, Scorrano, Luca, Wurst, Wolfgang, Morais, Vanessa A., Verstreken, Patrik, Smet, Joél

2009

Overview

Mutations of the mitochondrial PTEN (phosphatase and tensin homologue)‐induced kinase1 (PINK1) are important causes of recessive Parkinson disease (PD). Studies on loss of function and overexpression implicate PINK1 in apoptosis, abnormal mitochondrial morphology, impaired dopamine release and motor deficits. However, the fundamental mechanism underlying these various phenotypes remains to be clarified. Using fruit fly and mouse models we show that PINK1 deficiency or clinical mutations impact on the function of Complex I of the mitochondrial respiratory chain, resulting in mitochondrial depolarization and increased sensitivity to apoptotic stress in mammalian cells and tissues. In Drosophila neurons, PINK1 deficiency affects synaptic function, as the reserve pool of synaptic vesicles is not mobilized during rapid stimulation. The fundamental importance of PINK1 for energy maintenance under increased demand is further corroborated as this deficit can be rescued by adding ATP to the synapse. The clinical relevance of our observations is demonstrated by the fact that human wild type PINK1, but not PINK1 containing clinical mutations, can rescue Complex 1 deficiency. Our work suggests that Complex I deficiency underlies, at least partially, the pathogenesis of this hereditary form of PD. As Complex I dysfunction is also implicated in sporadic PD, a convergence of genetic and environmental causes of PD on a similar mitochondrial molecular mechanism appears to emerge.

• Publisher: Nature Publishing Group UK,WILEY‐VCH Verlag,EMBO Press,WILEY-VCH Verlag
• Subject: Animal models / Animals / Apoptosis / Cell division / Complex I / Curie, Marie (1867-1934) / Depolarization / Digital cameras / Dopamine / Drosophila melanogaster - enzymology / Drosophila Proteins - deficiency / Drosophila Proteins - genetics / Electron Transport / Electron transport chain / Electron Transport Complex I - metabolism / Genes / Genetic engineering / Humans / Insects / Kinases / Labeling / Laboratory animals / Mammalian cells / Membrane Potential, Mitochondrial - physiology / Mice / Mitochondria / Mitochondria - enzymology / Mitochondria - pathology / Mitochondria - ultrastructure / Mitochondrial DNA / mitochondrial dysfunction / Movement disorders / Mutation / Mutation - genetics / Neurodegenerative diseases / Neurons / Oxidative stress / Parkinson Disease - enzymology / Parkinson Disease - genetics / Parkinson Disease - pathology / Parkinson Disease - physiopathology / Parkinson's disease / Phenotypes / Protein Kinases - deficiency / Protein Kinases - genetics / Protein Serine-Threonine Kinases - deficiency / Protein Serine-Threonine Kinases - genetics / Proteins / PTEN protein / PTEN-induced putative kinase / Research Article / reserve pool deficit / Studies / Synapses / Synapses - enzymology / Synapses - pathology / Synapses - ultrastructure / Synaptic Transmission - physiology / Synaptic vesicles / Tensin