Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2008; 28(2):425-33. DOI: 10.1523/JNEUROSCI.3602-07.2008
Source: PubMed


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.

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Available from: Xiaoxi Zhuang, Aug 28, 2015
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    • "In a previous study, Chen et al. (2008) showed that ectopic expression of DAT in GABAergic striatal neurons leads to progressive cell loss and oxidative protein modifications. These results indicated that ectopic DAT expression in non-dopaminergic neurons is deleterious since these cells do not possess the capacity to efficiently metabolize or store dopamine in vesicles. "
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    ABSTRACT: The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "The plant was reported to have analgesic activity [10], antibacterial activity [11], hepatoprotective activity [12], antihypercholesterolemic activity [13], antiinflammatory activity [14], antidiabetic and antihyperlipidemic activity [15], anticataleptic activity [16], and antimicrobial [17] activity. Previous study indicates that Parkinson's disease occurs due to the increased oxidative stress [18] and several plants with antioxidant activity have been found to be effective in the treatment of disease [8]. Thus the study aimed at screening of the plant for its anti-Parkinson's activity. "
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    • "In vitro experiments suggest that the relative vulnerability of dopamine neurons in PD may be mediated by cytosolic dopamine (Mosharov et al., 2009). Furthermore, mice that express DAT on non-dopaminergic striatal neurons, which lack VMAT2, take up dopamine into those neurons, but do not store it in vesicles, producing motor deficits and profound striatal neurodegeneration , accompanied by markers of increased dopamine oxidation (Chen et al., 2008). Additionally, transgenic mice with altered expression of VMAT2 have illustrated the critical nature of vesicular storage of dopamine for the integrity of the nigrostriatal system. "
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    ABSTRACT: Active transport of neurotransmitters into synaptic vesicles is required for their subsequent exocytotic release. In the monoamine system, this process is carried out by the vesicular monoamine transporters (VMAT1 and VMAT2). These proteins are responsible for vesicular packaging of dopamine, norepinephrine, serotonin, and histamine. These proteins are essential for proper neuronal function; however, compared to their plasma membrane counterparts, there are few drugs available that target these vesicular proteins. This is partly due to the added complexity of crossing the plasma membrane, but also to the technical difficulty of assaying for vesicular uptake in high throughput. Until recently, reagents to enable high throughput screening for function of these vesicular neurotransmitter transporters have not been available. Fortunately, novel compounds and methods are now making such screening possible; thus, a renewed focus on these transporters as potential targets is timely and necessary.
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