RT Journal Article SR Electronic T1 Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 425 OP 433 DO 10.1523/JNEUROSCI.3602-07.2008 VO 28 IS 2 A1 Linan Chen A1 Yunmin Ding A1 Barbara Cagniard A1 Amber D. Van Laar A1 Amanda Mortimer A1 Wanhao Chi A1 Teresa G. Hastings A1 Un Jung Kang A1 Xiaoxi Zhuang YR 2008 UL http://www.jneurosci.org/content/28/2/425.abstract AB The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the “DOPA-sparing” clinical practice that avoids using l-3,4-dihydroxyphenylalanine (l-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover, l-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the first in vivo evidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficient in vivo approach to test therapeutic agents for PD.