Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin.
Degeneration of dopaminergic neurons in the substantia nigra is characteristic for Parkinson's disease (PD), the second most common neurodegenerative disorder. Mitochondrial dysfunction is believed to contribute to the etiology of PD. Although most cases are sporadic, recent evidence points to a number of genes involved in familial variants of PD. Among them, a loss-of-function of phosphatase and tensin homolog-induced kinase 1 (PINK1; PARK6) is associated with rare cases of autosomal recessive parkinsonism. In HeLa cells, RNA interference-mediated downregulation of PINK1 results in abnormal mitochondrial morphology and altered membrane potential. Morphological changes of mitochondria can be rescued by expression of wild-type PINK1 but not by PD-associated PINK1 mutants. Moreover, primary cells derived from patients with two different PINK1 mutants showed a similar defect in mitochondrial morphology. Human parkin but not PD-associated mutants could rescue mitochondrial pathology in human cells like wild-type PINK1. Our results may therefore suggest that PINK1 deficiency in humans results in mitochondrial abnormalities associated with cellular stress, a pathological phenotype, which can be ameliorated by enhanced expression of parkin.
Exner
Nicole
N
Center for Integrated Protein Science Munich and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany.
Treske
Bettina
B
Paquet
Dominik
D
Holmström
Kira
K
Schiesling
Carola
C
Gispert
Suzana
S
Carballo-Carbajal
Iria
I
Berg
Daniela
D
Hoepken
Hans-Hermann
HH
Gasser
Thomas
T
Krüger
Rejko
R
Winklhofer
Konstanze F
KF
Vogel
Frank
F
Reichert
Andreas S
AS
Auburger
Georg
G
Kahle
Philipp J
PJ
Schmid
Bettina
B
Haass
Christian
C
D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein