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Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin

Naturevolume 441pages11571161 (2006) | Download Citation

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Abstract

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration1,2. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of Drosophila PTEN-induced putative kinase 1 (PINK1 )3, a novel AR-JP-linked gene4. Here, we show that PINK1 mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl-2 demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of PINK1 mutants. Notably, we also found that PINK1 mutants share marked phenotypic similarities with parkin mutants. Transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.

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Acknowledgements

We would like to thank H. Richardson, H. J. Bellen, A. Pilling, W. Saxton, T. Adachi-Yamada, E. N. Olson, S. Birman, S. Noselli, E. J. Rulifson and G. M. Rubin for fly stocks. We appreciate B. Graham for helping us to get the effective anti-TH antibodies. We also thank the Korea Basic Science Institute for the use of SEM and TEM electron microscopes. We also thank members of the Chung laboratory for discussions. J.C. is grateful to J. Blenis for his encouragement.

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Author notes

  1. Jeehye Park and Sung Bae Lee: *These authors contributed equally to this work

Affiliations

  1. National Creative Research Initiatives Center for Cell Growth Regulation

    • Jeehye Park
    • , Sung Bae Lee
    • , Sungkyu Lee
    • , Yongsung Kim
    • , Saera Song
    • , Sunhong Kim
    •  & Jongkyeong Chung
  2. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong-Gu, Taejon, 305-701, Korea

    • Jeehye Park
    • , Sung Bae Lee
    • , Sungkyu Lee
    • , Yongsung Kim
    • , Saera Song
    • , Sunhong Kim
    • , Jaeseob Kim
    •  & Jongkyeong Chung
  3. GenExel, Inc., 373-1 Kusong-Dong, Yusong-Gu, Taejon, 305-701, Korea

    • Eunkyung Bae
    •  & Jaeseob Kim
  4. Department of Internal Medicine

    • Minho Shong
  5. Department of Pathology, Chungnam National University School of Medicine, 640 Daesa-Dong, Chung-Gu, Taejon, 301-721, Korea

    • Jin-Man Kim

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Jongkyeong Chung.

Supplementary information

  1. Supplementary Notes

    This file contains the Supplementary Methods and Supplementary Figure Legends. (DOC 109 kb)

  2. Supplementary Figures

    This file contains Supplementary Figures 1–8. (PDF 1247 kb)

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https://doi.org/10.1038/nature04788

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