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-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease
,1
* Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA;
Department of Neurology, First Clinical Hospital,
Department of Physiology, Dalian Medical University, Dalian, China; and
Department of Pathology, University of Washington, Seattle, Washington, USA
1Correspondence: Division of Neuropathology, Harborview Medical Center, University of Washington School of Medicine, 703C Research and Training Bldg., Campus Box 359635, 325 9th Ave., Seattle, WA 98104-2499, USA. E-mail: zhangj{at}u.washington.edu
A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson’s disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of 
-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human -synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated -synuclein. Furthermore, microglial enhancement of -synuclein-mediated neurotoxicity depended on phagocytosis of -synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated -synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in -synuclein-mediated microglial activation and associated neurotoxicity.—Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J. S., Zhang, J. Aggregated -synuclein activates microglia: a process leading to disease progression in Parkinson’s disease.
Key Words: microglia • phagocytosis • innate immunity • aging • oxidative stress • protein aggregation • inflammation
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