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The Journal of Neuroscience, August 8, 2007, 27(32):8563-8570; doi:10.1523/JNEUROSCI.0218-07.2007

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Neurobiology of Disease
Drosophila Overexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

Cheng Wang,^1,3,4 Ruifeng Lu,^3,4 Xuezhi Ouyang,³ Michelle W. L. Ho,¹ William Chia,^3,4 Fengwei Yu,^3,4 and Kah-Leong Lim^1,2,4

¹Neurodegeneration Research Laboratory and ²Parkinson's Disease and Movement Disorders Center, National Neuroscience Institute, Singapore 308433, and ³Temasek Life Sciences Laboratory and ⁴Department of Biological Sciences, National University of Singapore, Singapore 117604

Correspondence should be addressed to either of the following: Dr. Kah-Leong Lim, Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Email: kah_leong_lim{at}nni.com.sg; or Dr. Fengwei Yu, Molecular Neurogenesis Group, Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Email: fengwei{at}tll.org.sg

Mutations in the parkin gene are a predominant cause of familial parkinsonism. Although initially described as a recessive disorder, emerging evidence suggest that single parkin mutations alone may confer increased susceptibility to Parkinson's disease. To better understand the effects of parkin mutations in vivo, we generated transgenic Drosophila overexpressing two human parkin missense mutants, R275W and G328E. Transgenic flies that overexpress R275W, but not wild-type or G328E, human parkin display an age-dependent degeneration of specific dopaminergic neuronal clusters and concomitant locomotor deficits that accelerate with age or in response to rotenone treatment. Furthermore, R275W mutant flies also exhibit prominent mitochondrial abnormalities in their flight muscles. Interestingly, these defects caused by the expression of human R275W parkin are highly similar to those triggered by the loss of endogenous parkin in parkin null flies. Together, our results provide the first in vivo evidence demonstrating that parkin R275W mutant expression mediates pathogenic outcomes and suggest the interesting possibility that select parkin mutations may directly exert neurotoxicity in vivo.

Key words: Parkinson's disease; ubiquitin; proteasome; rotenone; neurotoxicity; neuronal death

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Received Sept. 15, 2006; revised June 26, 2007; accepted June 29, 2007.

Correspondence should be addressed to either of the following: Dr. Kah-Leong Lim, Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Email: kah_leong_lim{at}nni.com.sg; or Dr. Fengwei Yu, Molecular Neurogenesis Group, Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Email: fengwei{at}tll.org.sg

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