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Author Notes:

GaryW. Miller, Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, Room 505K, 615 Michael Street, Atlanta, GA 30322. E-mail: gary.miller@emory.edu.

We thank Dr. Randy Hall for his critical reading and helpful comments regarding the preparation of this manuscript.

Subjects:

Research Funding:

This work was supported by the Emory Collaborative Center for Parkinson's Disease Environmental Research U54ES012068 and American Parkinson's Disease Association (G.W.M.); and National Institutes of Health Grants T32ES012870 (W.M.C.); F32ES013457 and R21ES013828 (J.R.R.); ES010806 and ES12077 (D.A.D.); an Environmental Protection Agency Science to Achieve Results Fellowship (T.S.G.); Parkinson's Disease (United Kingdom) Grant 4039 (P.C.E.); and a Medical Research Council Cooperative Award in Science and Enginineering studentship with Sanofi-Aventis (R.E.C.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Parkinson's disease
  • vesicular monoamine transporter 2
  • dopamine
  • neurodegeneration
  • dopamine transporter
  • tyrosine hydroxylase
  • MONOAMINE TRANSPORTER VMAT2
  • HETEROZYGOTE KNOCKOUT MICE
  • HUMAN ALPHA-SYNUCLEIN
  • PARKINSONS-DISEASE
  • IMMUNOCHEMICAL ANALYSIS
  • HERBICIDE PARAQUAT
  • SUBSTANTIA-NIGRA
  • MOUSE MODEL
  • NEURONS
  • PROTEIN

Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 27, Number 30

Publisher:

, Pages 8138-8148

Type of Work:

Article | Final Publisher PDF

Abstract:

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,weobserved an increase in α-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, α-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.

Copyright information:

Copyright © 2007 Society for Neuroscience.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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