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Neurobiol Dis. 2015 Feb;74:66-75. doi: 10.1016/j.nbd.2014.10.016. Epub 2014 Oct 30.

Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.

Author information

1
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: shababa.masoud@mail.utoronto.ca.
2
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: laura.vecchio@mail.utoronto.ca.
3
Department of Medical Biology, Université du Québec à Trois-Rivières, QC G9A 5H7 Canada. Electronic address: yan.bergeron@uqtr.ca.
4
Environmental and Occupational Health Sciences Institute, Rutgers, 170 Frelinghuysen Road, EOHSI 340, Piscataway, NJ 08854, USA. Electronic address: mhossain@eohsi.rutgers.edu.
5
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: Lien.nguyen@mail.utoronto.ca.
6
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: kristel.bermejo@mail.utoronto.ca.
7
Department of Chemistry, University of North Carolina at Chapel Hill, NC 27599, USA. Electronic address: bkile04@gmail.com.
8
Neuroscience and Brain Technologies, Italian Institute of Technology, Via Morego 30, Genova 16163, Italy; Faculty of Biology and Soil Science, St. Petersburg State University, St. Petersburg 199034, Russia. Electronic address: tatiana.sotnikova@iit.it.
9
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: billsiesser@gmail.com.
10
Neuroscience and Brain Technologies, Italian Institute of Technology, Via Morego 30, Genova 16163, Italy; Faculty of Biology and Soil Science, St. Petersburg State University, St. Petersburg 199034, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143025 Moscow Region, Russia. Electronic address: Raul.Gainetdinov@iit.it.
11
Department of Chemistry, University of North Carolina at Chapel Hill, NC 27599, USA. Electronic address: rmw@unc.edu.
12
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: marc.caron@duke.edu.
13
Environmental and Occupational Health Sciences Institute, Rutgers, 170 Frelinghuysen Road, EOHSI 340, Piscataway, NJ 08854, USA. Electronic address: jricha3@eohsi.rutgers.edu.
14
Department of Environmental Health, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address: gwmille@emory.edu.
15
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: a.ramsey@utoronto.ca.
16
Department of Medical Biology, Université du Québec à Trois-Rivières, QC G9A 5H7 Canada. Electronic address: Michel.Cyr@uqtr.ca.
17
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle - Rm 4302, Toronto, ON M5S 1A8, Canada. Electronic address: ali.salahpour@utoronto.ca.

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.

KEYWORDS:

Cytosolic dopamine; Dopamine neuron loss; Dopamine transporter; MPTP; Motor deficits; Oxidative stress; Parkinson's disease; Transgenic mice; l-DOPA

PMID:
25447236
PMCID:
PMC4505366
DOI:
10.1016/j.nbd.2014.10.016
[Indexed for MEDLINE]
Free PMC Article

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