Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 30, Pages 8138-8148Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0319-07.2007
Keywords
Parkinson's disease; vesicular monoamine transporter 2; dopamine; neurodegeneration; dopamine transporter; tyrosine hydroxylase
Categories
Funding
- NIEHS NIH HHS [U54 ES012068, F32ES013457, R21ES013828, ES12077, U54ES012068, U54 ES012077, R01 ES010806, T32ES012870, ES010806, R21 ES013828, F32 ES013457, T32 ES012870] Funding Source: Medline
- Parkinson's UK [G-4039] Funding Source: Medline
Ask authors/readers for more resources
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 similar to 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 alpha-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, a-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available