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The Journal of Neuroscience, February 18, 2009, 29(7):1962-1976; doi:10.1523/JNEUROSCI.5351-08.2009

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Neurobiology of Disease
Bacterial Artificial Chromosome Transgenic Mice Expressing a Truncated Mutant Parkin Exhibit Age-Dependent Hypokinetic Motor Deficits, Dopaminergic Neuron Degeneration, and Accumulation of Proteinase K-Resistant -Synuclein

Xiao-Hong Lu,^1,2,3 Sheila M. Fleming,⁵ Bernhard Meurers,⁵ Larry C. Ackerson,^2,3 Farzad Mortazavi,⁵ Victor Lo,^1,2,3 Daniela Hernandez,^6,7 David Sulzer,^6,7 George R. Jackson,^1,3,5 Nigel T. Maidment,^2,3 Marie-Francoise Chesselet,^3,4,5 and X. William Yang^1,2,3

¹Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, ²Department of Psychiatry and Biobehavioral Sciences, ³Brain Research Institute, and Departments of ⁴Neurobiology and ⁵Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, and ⁶Departments of Neurology and ⁷Psychiatry, Columbia University, New York, New York 10032

Correspondence should be addressed to X. William Yang at the above address. Email: xwyang{at}mednet.ucla.edu

Recessive mutations in parkin are the most common cause of familial early-onset Parkinson's disease (PD). Recent studies suggest that certain parkin mutants may exert dominant toxic effects to cultured cells and such dominant toxicity can lead to progressive dopaminergic (DA) neuron degeneration in Drosophila. To explore whether mutant parkin could exert similar pathogenic effects to mammalian DA neurons in vivo, we developed a BAC (bacterial artificial chromosome) transgenic mouse model expressing a C-terminal truncated human mutant parkin (Parkin-Q311X) in DA neurons driven by a dopamine transporter promoter. Parkin-Q311X mice exhibit multiple late-onset and progressive hypokinetic motor deficits. Stereological analyses reveal that the mutant mice develop age-dependent DA neuron degeneration in substantia nigra accompanied by a significant loss of DA neuron terminals in the striatum. Neurochemical analyses reveal a significant reduction of the striatal dopamine level in mutant mice, which is significantly correlated with their hypokinetic motor deficits. Finally, mutant Parkin-Q311X mice, but not wild-type controls, exhibit age-dependent accumulation of proteinase K-resistant endogenous -synuclein in substantia nigra and colocalized with 3-nitrotyrosine, a marker for oxidative protein damage. Hence, our study provides the first mammalian genetic evidence that dominant toxicity of a parkin mutant is sufficient to elicit age-dependent hypokinetic motor deficits and DA neuron loss in vivo, and uncovers a causal relationship between dominant parkin toxicity and progressive -synuclein accumulation in DA neurons. Our study underscores the need to further explore the putative link between parkin dominant toxicity and PD.

Key words: Parkinson's disease; dopaminergic; transgenic; mice; neuron death; neuropathology

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Received Nov. 6, 2008; revised Nov. 19, 2008; accepted Dec. 16, 2008.

Correspondence should be addressed to X. William Yang at the above address. Email: xwyang{at}mednet.ucla.edu

Related articles in J. Neurosci.:

Mice Expressing Mutant Parkin Exhibit Hallmark Features of Parkinson's Disease

Michael P. Hart and Acong Xu
J. Neurosci. 2009 29: 7392-7394. [Full Text]  

This article has been cited by other articles:

				M. P. Hart and A. Xu Mice Expressing Mutant Parkin Exhibit Hallmark Features of Parkinson's Disease J. Neurosci., June 10, 2009; 29(23): 7392 - 7394. [Full Text] [PDF]

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