1. National Creative Research Initiatives Center for Cell Growth Regulation, and
2. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong-Gu, Taejon 305-701, Korea
3. GenExel, Inc., 373-1 Kusong-Dong, Yusong-Gu, Taejon 305-701, Korea
4. Department of Internal Medicine, and
5. Department of Pathology, Chungnam National University School of Medicine, 640 Daesa-Dong, Chung-Gu, Taejon 301-721, Korea
6. *These authors contributed equally to this work

Correspondence to: Jongkyeong Chung^1,2 Correspondence and requests for materials should be addressed to J.C. (Email: jchung@kaist.ac.kr).

Abstract

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration^{1, 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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