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The Journal of Neuroscience, January 31, 2007, 27(5):981-992; doi:10.1523/JNEUROSCI.4810-06.2007

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Neurobiology of Disease
A Drosophila Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine

Tzu-Kang Sang,^1,2 * Hui-Yun Chang,^3 * George M. Lawless,¹ Anuradha Ratnaparkhi,¹ Lisa Mee,¹ Larry C. Ackerson,³ Nigel T. Maidment,^3,4,5,6 David E. Krantz,^3,4,5 and George R. Jackson^1,4,6

¹Neurogenetics and Movement Disorders Programs, Department of Neurology, and ²Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Taiwan, Republic of China, and ³Department of Psychiatry and Biobehavioral Sciences, ⁴Brain Research Institute, ⁵Hatos Center for Neuropharmacology, and ⁶Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to either George R. Jackson or David E. Krantz, Gonda (Goldschmied) Neuroscience and Genetics Research Center, 695 Charles E. Young Drive South, University of California Los Angeles, Los Angeles, CA 90095. Email: grjackson{at}mednet.ucla.edu or Email: dkrantz{at}ucla.edu

Mutations in human parkin have been identified in familial Parkinson's disease and in some sporadic cases. Here, we report that expression of mutant but not wild-type human parkin in Drosophila causes age-dependent, selective degeneration of dopaminergic (DA) neurons accompanied by a progressive motor impairment. Overexpression or knockdown of the Drosophila vesicular monoamine transporter, which regulates cytosolic DA homeostasis, partially rescues or exacerbates, respectively, the degenerative phenotypes caused by mutant human parkin. These results support a model in which the vulnerability of DA neurons to parkin-induced neurotoxicity results from the interaction of mutant parkin with cytoplasmic dopamine.

Key words: dopaminergic; Drosophila; monoamine; aging (ageing); neuroprotection; neuronal death

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Received May 29, 2006; revised Dec. 8, 2006; accepted Dec. 10, 2006.

Correspondence should be addressed to either George R. Jackson or David E. Krantz, Gonda (Goldschmied) Neuroscience and Genetics Research Center, 695 Charles E. Young Drive South, University of California Los Angeles, Los Angeles, CA 90095. Email: grjackson{at}mednet.ucla.edu or Email: dkrantz{at}ucla.edu

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