TY - JOUR
T1 - Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin
AU - Exner, Nicole
AU - Treske, Bettina
AU - Paquet, Dominik
AU - Holmström, Kira
AU - Schiesling, Carola
AU - Gispert, Suzana
AU - Carballo-Carbajal, Iria
AU - Berg, Daniela
AU - Hoepken, Hans Hermann
AU - Gasser, Thomas
AU - Krüger, Rejko
AU - Winklhofer, Konstanze F.
AU - Vogel, Frank
AU - Reichert, Andreas S.
AU - Auburger, Georg
AU - Kahle, Philipp J.
AU - Schmid, Bettina
AU - Haass, Christian
PY - 2007/11/7
Y1 - 2007/11/7
N2 - 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 anumber 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.
AB - 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 anumber 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.
KW - Familial Parkinson's disease
KW - Loss-of-function
KW - Mitochondria
KW - Neurodegeneration
KW - PINK1
KW - Parkin
UR - http://www.scopus.com/inward/record.url?scp=36049038504&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0719-07.2007
DO - 10.1523/JNEUROSCI.0719-07.2007
M3 - Article
C2 - 17989306
AN - SCOPUS:36049038504
SN - 0270-6474
VL - 27
SP - 12413
EP - 12418
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 45
ER -