QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (63) Citing Articles via Google Scholar Google Scholar Articles by Exner, N. Articles by Haass, C. Search for Related Content PubMed PubMed Citation Articles by Exner, N. Articles by Haass, C.

 Previous Article  |  Next Article 

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

---

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

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2007 27: i. [Full Text]  

This article has been cited by other articles:

				D. Sha, L.-S. Chin, and L. Li Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-{kappa}B signaling Hum. Mol. Genet., November 11, 2009; (2009) ddp501v2. [Abstract] [Full Text] [PDF]

				O. Rothfuss, H. Fischer, T. Hasegawa, M. Maisel, P. Leitner, F. Miesel, M. Sharma, A. Bornemann, D. Berg, T. Gasser, et al. Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair Hum. Mol. Genet., October 15, 2009; 18(20): 3832 - 3850. [Abstract] [Full Text] [PDF]

				H. Chen and D. C. Chan Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases Hum. Mol. Genet., October 15, 2009; 18(R2): R169 - R176. [Abstract] [Full Text] [PDF]

				A. K. Lutz, N. Exner, M. E. Fett, J. S. Schlehe, K. Kloos, K. Lammermann, B. Brunner, A. Kurz-Drexler, F. Vogel, A. S. Reichert, et al. Loss of Parkin or PINK1 Function Increases Drp1-dependent Mitochondrial Fragmentation J. Biol. Chem., August 21, 2009; 284(34): 22938 - 22951. [Abstract] [Full Text] [PDF]

				S. Saha, M. D. Guillily, A. Ferree, J. Lanceta, D. Chan, J. Ghosh, C. H. Hsu, L. Segal, K. Raghavan, K. Matsumoto, et al. LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans J. Neurosci., July 22, 2009; 29(29): 9210 - 9218. [Abstract] [Full Text] [PDF]

				X. Wang, B. Su, H.-g. Lee, X. Li, G. Perry, M. A. Smith, and X. Zhu Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease J. Neurosci., July 15, 2009; 29(28): 9090 - 9103. [Abstract] [Full Text] [PDF]

				J. Park, Y. Kim, and J. Chung Mitochondrial dysfunction and Parkinson's disease genes: insights from Drosophila Dis. Model. Mech., July 1, 2009; 2(7-8): 336 - 340. [Abstract] [Full Text] [PDF]

				J. Samann, J. Hegermann, E. von Gromoff, S. Eimer, R. Baumeister, and E. Schmidt Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth J. Biol. Chem., June 12, 2009; 284(24): 16482 - 16491. [Abstract] [Full Text] [PDF]

				R. K. Dagda, S. J. Cherra III, S. M. Kulich, A. Tandon, D. Park, and C. T. Chu Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission J. Biol. Chem., May 15, 2009; 284(20): 13843 - 13855. [Abstract] [Full Text] [PDF]

				T. Gasser Genomic and proteomic biomarkers for Parkinson disease Neurology, February 17, 2009; 72(7_Supplement_2): S27 - S31. [Abstract] [Full Text] [PDF]

				J. Yun, J. H. Cao, M. W. Dodson, I. E. Clark, P. Kapahi, R. B. Chowdhury, and M. Guo Loss-of-Function Analysis Suggests That Omi/HtrA2 Is Not an Essential Component of the pink1/parkin Pathway In Vivo J. Neurosci., December 31, 2008; 28(53): 14500 - 14510. [Abstract] [Full Text] [PDF]

				X. Wang, B. Su, S. L. Siedlak, P. I. Moreira, H. Fujioka, Y. Wang, G. Casadesus, and X. Zhu Amyloid-{beta} overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins PNAS, December 9, 2008; 105(49): 19318 - 19323. [Abstract] [Full Text] [PDF]

				D. Narendra, A. Tanaka, D.-F. Suen, and R. J. Youle Parkin is recruited selectively to impaired mitochondria and promotes their autophagy J. Cell Biol., December 1, 2008; 183(5): 795 - 803. [Abstract] [Full Text] [PDF]

				H. M. McBride Parkin mitochondria in the autophagosome J. Cell Biol., December 1, 2008; 183(5): 757 - 759. [Abstract] [Full Text] [PDF]

				H. Deng, M. W. Dodson, H. Huang, and M. Guo The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila PNAS, September 23, 2008; 105(38): 14503 - 14508. [Abstract] [Full Text] [PDF]

				A. J. Whitworth, J. R. Lee, V. M.-W. Ho, R. Flick, R. Chowdhury, and G. A. McQuibban Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin Dis. Model. Mech., September 1, 2008; 1(2-3): 168 - 174. [Abstract] [Full Text] [PDF]

				C. Zhou, Y. Huang, Y. Shao, J. May, D. Prou, C. Perier, W. Dauer, E. A. Schon, and S. Przedborski The kinase domain of mitochondrial PINK1 faces the cytoplasm PNAS, August 19, 2008; 105(33): 12022 - 12027. [Abstract] [Full Text] [PDF]

				H. Plun-Favreau and J. Hardy PINK1 in mitochondrial function PNAS, August 12, 2008; 105(32): 11041 - 11042. [Full Text] [PDF]

				X. Wang, B. Su, H. Fujioka, and X. Zhu Dynamin-Like Protein 1 Reduction Underlies Mitochondrial Morphology and Distribution Abnormalities in Fibroblasts from Sporadic Alzheimer's Disease Patients Am. J. Pathol., August 1, 2008; 173(2): 470 - 482. [Abstract] [Full Text] [PDF]

				J. S. Schlehe, A. K. Lutz, A. Pilsl, K. Lammermann, K. Grgur, I. H. Henn, J. Tatzelt, and K. F. Winklhofer Aberrant Folding of Pathogenic Parkin Mutants: AGGREGATION VERSUS DEGRADATION J. Biol. Chem., May 16, 2008; 283(20): 13771 - 13779. [Abstract] [Full Text] [PDF]

				Y. Yang, Y. Ouyang, L. Yang, M. F. Beal, A. McQuibban, H. Vogel, and B. Lu Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery PNAS, May 13, 2008; 105(19): 7070 - 7075. [Abstract] [Full Text] [PDF]

				A. C. Poole, R. E. Thomas, L. A. Andrews, H. M. McBride, A. J. Whitworth, and L. J. Pallanck The PINK1/Parkin pathway regulates mitochondrial morphology PNAS, February 5, 2008; 105(5): 1638 - 1643. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help