| Abstract No.: | C-B3073 |
| Country: | USA |
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| Title: | SELECTIVE CELL DEATH IN DOPAMINERGIC NEURONS IS MEDIATED BY ASTROCYTES THROUGH THE EXTRANEURONAL MONOAMINE TRANSPORTER IN A MOUSE MODEL OF PARKINSON’S DISEASE |
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| Authors/Affiliations: | Aras R1, Cui M1, Hatwar M1, Rappold P1, Panza J1, Peng W2,3, Jackson-Lewis V4, Ballatori N1. Javitch JA4, Nedergaard M2,3, Przedborski S4, Tieu K1,2
1Dept. of Environmental Medicine, New York, NY, USA, 2Center of Aging and Developmental Biology, Rochester, NY, USA, and 3Dept. of Neurosurgery, University of Rochester, NY. 4Dept. Of Neurology, Columbia University, NY, USA
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| Content: | Objectives: Astrocytes are increasingly being recognized as playing critical roles in maintaining normal physiological functions as well as in inducing and aggravating neuronal pathology. The neuroprotective and neurodegenerative roles of astrocytes depend largely on the molecules that they remove from or release into the extracellular microenvironment that is shared by astrocytes and neurons. Recently, the extraneuronal monoamine transporter, also known as the organic cation transporter-3 (OCT3) in rodents, was shown to be expressed in astrocytes. The present study tested the hypothesis that astrocytes modulate neurodegeneration by regulating the levels of toxic cations in the extracellular space of neurons in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease
Materials, Methods and Results: Immunohistochemical analyses in C57BL mice showed that OCT3 was selectively expressed in astrocytes in the nigrostriatal region but not in the astrocytes that reside in the cerebellum, hippocampus, cortex and locus coeruleus. Similar pattern of expression was also detected in post-mortem human brain sections. Functional transport studies in cultured primary astrocytes and cells stably overexpressing OCT3 confirmed bi-directional transport of [3H]-MPP+ (1-methyl-4-phenylpyridinium) mediated by OCT3, thus supporting its ability to modulate the levels of certain organic cations. To assess the role of astrocytic OCT3 in dopaminergic cell death, C57BL mice were injected with MPTP, a parkinsonian neurotoxicant, to introduce the cation MPP+ (the active metabolite of MPTP) into astrocytes. Data obtained from in vivo microdialysis in free moving mice injected with MPTP showed extracellular striatal levels of MPP+ were significantly lower in mice with OCT3 deficient than those in the wild type littermates. Stereological cell counts of dopaminergic neurons in the substantia nigra showed significantly less cell death in OCT3-knockout mice and in animals treated with an OCT3 inhibitor, as compared to their respective MPTP treated controls.
Conclusion: This study provides insight into a novel mechanism that contributes to selective cell death, as observed in the MPTP animal model of Parkinson’s disease (Supported in part by NIH Grants RO1-ES014899, P3- ES01247, and T32-ES07026).
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