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The Journal of Neuroscience, November 7, 2007, 27(45):12413-12418; doi:10.1523/JNEUROSCI.0719-07.2007

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Neurobiology of Disease
Loss-of-Function of Human PINK1 Results in Mitochondrial Pathology and Can Be Rescued by Parkin

Nicole Exner,¹ Bettina Treske,¹ Dominik Paquet,¹ Kira Holmström,² Carola Schiesling,² Suzana Gispert,³ Iria Carballo-Carbajal,² Daniela Berg,² Hans-Hermann Hoepken,³ Thomas Gasser,² Rejko Krüger,² Konstanze F. Winklhofer,⁴ Frank Vogel,⁵ Andreas S. Reichert,^6,7 Georg Auburger,³ Philipp J. Kahle,^1,2 Bettina Schmid,¹ and Christian Haass¹

¹Center 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, ²Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany, ³Section of Molecular Neurogenetics, Department of Neurology, Johann Wolfgang Goethe University Medical School, 60590 Frankfurt, Germany, ⁴Adolf-Butenandt-Institute, Department of Biochemistry, Neurobiochemistry Group, Ludwig-Maximilians-University, 80336 Munich, Germany, ⁵Max-Delbrück-Center for Molecular Medicine, 13092 Berlin, Germany, ⁶Adolf-Butenandt-Institute, Physiological Chemistry, Ludwig-Maximilians-University, 81377 Munich, Germany, and ⁷Cluster of Excellence Macromolecular Complexes, Mitochondrial Biology, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany

Correspondence should be addressed to Dr. Christian Haass, Department of Biochemistry, Adolf-Butenandt-Institute, Schillerstrasse 44, 80336 Munich, Germany. Email: chaass{at}med.uni-muenchen.de

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.

Key words: neurodegeneration; familial Parkinson's disease; PINK1; loss-of-function; mitochondria; parkin

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Received Feb. 16, 2007; revised Sept. 25, 2007; accepted Sept. 28, 2007.

Correspondence should be addressed to Dr. Christian Haass, Department of Biochemistry, Adolf-Butenandt-Institute, Schillerstrasse 44, 80336 Munich, Germany. Email: chaass{at}med.uni-muenchen.de

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