Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein

Authors

  • Wei Zhang,

    1. Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
    2. Department of Neurology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
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  • Shannon Dallas,

    1. Intracellular Regulation Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • Dan Zhang,

    1. Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • Jian-Ping Guo,

    1. Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada
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  • Hao Pang,

    1. Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • Belinda Wilson,

    1. Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • David S. Miller,

    1. Intracellular Regulation Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • Biao Chen,

    1. Department of Neurology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing, China
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  • Wanqin Zhang,

    1. Department of Physiology, Dalian Medical University, Dalian, China
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  • Patrick L. McGeer,

    1. Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada
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  • Jau-Shyong Hong,

    1. Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina
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  • Jing Zhang

    Corresponding author
    1. Department of Pathology, University of Washington, Seattle, Washington
    • Division of Neuropathology, Harborview Medical Center, University of Washington School of Medicine, Box 359635, 325 9th Avenue, Seattle, WA 98104-2499, USA
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Abstract

α-Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant α-synuclein has been attributed to date largely to faster formation of α-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) α-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated α-synuclein could activate microglia more powerfully than WT α-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that α-synuclein with the A30P or A53T mutations caused greater microglial activation than WT α-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant α-synuclein. Mutant α-synuclein also induced greater production of reactive oxygen species than WT α-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than α-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant α-synuclein. © 2007 Wiley-Liss, Inc.

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