Aggregated α-synuclein activates microglia: A process leading to disease progression in Parkinson's disease

Wei Zhang, Tongguang Wang, Zhong Pei, David S. Miller, Xuefei Wu, Michelle L. Block, Belinda Wilson, Wanqin Zhang, Yong Zhou, Jau Shyong Hong, Jing Zhang

Research output: Contribution to journalArticle

717 Scopus citations


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 α-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 α-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated α-synuclein. Furthermore, microglial enhancement of α-synuclein-mediated neurotoxicity depended on phagocytosis of α-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 α-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 α-synuclein-mediated microglial activation and associated neurotoxicity.

Original languageEnglish (US)
Pages (from-to)533-542
Number of pages10
JournalFASEB Journal
Issue number6
StatePublished - Apr 1 2005



  • Aging
  • Inflammation
  • Innate immunity
  • Microglia
  • Oxidative stress
  • Phagocytosis
  • Protein aggregation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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. (2005). Aggregated α-synuclein activates microglia: A process leading to disease progression in Parkinson's disease. FASEB Journal, 19(6), 533-542.