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The Journal of Neuroscience, July 25, 2007, 27(30):8138-8148; doi:10.1523/JNEUROSCI.0319-07.2007

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Neurobiology of Disease
Reduced Vesicular Storage of Dopamine Causes Progressive Nigrostriatal Neurodegeneration

W. Michael Caudle,^1,2 Jason R. Richardson,^1,2,3 Min Z. Wang,^1,2 Tonya N. Taylor,^1,2 Thomas S. Guillot,^1,2 Alison L. McCormack,⁴ Rebecca E. Colebrooke,⁵ Donato A. Di Monte,⁴ Piers C. Emson,⁵ and Gary W. Miller^1,2

¹Center for Neurodegenerative Disease, ²Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, ³Department of Environmental and Occupational Medicine, University of Medicine and Dentistry-New Jersey/Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, ⁴The Parkinson's Institute, Sunnyvale, California 94089, and ⁵The Babraham Institute, Neurobiology Programme, Babraham, Cambridge CB2 4AT, United Kingdom

Correspondence should be addressed to Gary W. Miller, Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, Room 505K, 615 Michael Street, Atlanta, GA 30322. Email: gary.miller{at}emory.edu

The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express 5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts to L-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosine hydroxylase. Furthermore, we observed an increase in -synuclein immunoreactivity and accumulation and neurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, -synuclein accumulation, and an L-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson's disease. These data suggest that mishandling of dopamine via reduced VMAT2 expression is, in and of itself, sufficient to cause dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system. In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.

Key words: Parkinson's disease; vesicular monoamine transporter 2; dopamine; neurodegeneration; dopamine transporter; tyrosine hydroxylase

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Received Jan. 24, 2007; revised May 25, 2007; accepted June 21, 2007.

Correspondence should be addressed to Gary W. Miller, Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, Room 505K, 615 Michael Street, Atlanta, GA 30322. Email: gary.miller{at}emory.edu

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