Reactive microgliosis: Extracellular-calpain and microglia-mediated dopaminergic neurotoxicity

Shannon Levesque, Belinda Wilson, Vincent Gregoria, Laura B. Thorpe, Shannon Dallas, Vadim S. Polikov, Jau Shyong Hong, Michelle L. Block

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Microglia, the innate immune cells in the brain, can become chronically activated in response to dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which is implicated in the progressive nature of Parkinson's disease. Here, we use an in vitro approach to separate neuron injury factors from the cellular actors of reactive microgliosis and discover molecular signals responsible for chronic and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate oxidase.-Calpain was identified as a key signal released from damaged neurons, causing selective dopaminergic neuron death through activation of microglial nicotinamide adenine dinucleotide phosphate oxidase and superoxide production. These findings suggest that dopaminergic neurons may be inherently susceptible to the pro-inflammatory effects of neuron damage, i.e. reactive microgliosis, providing much needed insight into the chronic nature of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)808-821
Number of pages14
JournalBrain
Volume133
Issue number3
DOIs
StatePublished - Mar 1 2010
Externally publishedYes

Keywords

  • Chronic neurotoxicity
  • Extracellular-calpain
  • Inflammation-mediated neurodegeneration
  • Microglia
  • Oxidative stress
  • Parkinson's disease
  • Reactive microgliosis

ASJC Scopus subject areas

  • Clinical Neurology

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  • Cite this

    Levesque, S., Wilson, B., Gregoria, V., Thorpe, L. B., Dallas, S., Polikov, V. S., Hong, J. S., & Block, M. L. (2010). Reactive microgliosis: Extracellular-calpain and microglia-mediated dopaminergic neurotoxicity. Brain, 133(3), 808-821. https://doi.org/10.1093/brain/awp333