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Title: Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function
Authors: Morais, Vanessa
Verstreken, Patrik
Roethig, Anne
Smet, Joel
Snellinx, An
Vanbrabant, Mieke
Haddad, Dominik
Frezza, Christian
Mandemakers, Wilhelm
Vogt-Weisenhorn, Daniela
Van Coster, Rudy
Wurst, Wolfgang
Scorrano, Luca
De Strooper, Bart # ×
Issue Date: May-2009
Publisher: Wiley-Blackwell Publishing Ltd.
Series Title: EMBO Molecular Medicine vol:1 issue:2 pages:99-111
Abstract: 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.
ISSN: 1757-4676
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
Molecular Genetics Section (-)
Laboratory of Neuronal Communication
× corresponding author
# (joint) last author

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