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Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin

Clark, Ira E. and Dodson, Mark W. and Cao, Joseph H. and Huh, Jun R. and Seol, Jae Hong and Yoo, Soon Ji and Hay, Bruce A. and Guo, Ming (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441 (7097). pp. 1162-1166. ISSN 0028-0836. doi:10.1038/nature04779.

[img] Image (JPEG) (Supplementary Figure 1 Sequence alignment and expression pattern of pink1) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 2 Loss of pink1 function does not cause changes in the number of dopaminergic neurons in the brain) - Supplemental Material
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[img] Image (JPEG) (Supplementary Figure 3 pink1 flies have profound defects in flight behaviour) - Supplemental Material
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Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1–parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.

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Additional Information:© Nature Publishing Group. Received 15 February; accepted 7 April 2006; Published online 30 April 2006. We thank G. Mardon and L. Pallanck for parkin cDNA and mutant flies; A. Simon, D. Walker, X. Zhan and A. Kiger for technical advice; L. Zipursky, L. Toro and D. Krantz for access to equipment and space; Guo laboratory members for discussions; and the EM core facilities at UCLA Brain Research Institute and at Caltech. We are indebted to R. Young in Seymour Benzer's laboratory for assistance with EM, and F. Laski for his phase contrast microscope. This work was supported by a National Institute of Health (NIH) grant to B.A.H. and an Alfred P. Sloan Foundation Fellowship in Neuroscience and a NIH grant to M.G. Author Contributions I.E.C., M.W.D., C.J. and J.H.C. in the Guo laboratory conceived and performed the experiments. J.R.H. and B.A.H. in the Hay laboratory assisted with experiments involving TEM in testes and with TUNEL staining; J.H.S. and S.J.Y. provided crucial reagents; and M.G. conceived and performed experiments, supervised the work, and wrote the manuscript with helpful comments from B.A.H. and authors from the Guo laboratory.
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Alfred P. Sloan FoundationUNSPECIFIED
Issue or Number:7097
Record Number:CaltechAUTHORS:20150326-091216959
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Official Citation:Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., . . . Guo, M. (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. [10.1038/nature04779]. Nature, 441(7097), 1162-1166.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56113
Deposited On:27 Mar 2015 01:11
Last Modified:10 Nov 2021 20:54

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