Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity

Brain. 2010 Mar;133(Pt 3):808-21. doi: 10.1093/brain/awp333. Epub 2010 Jan 31.


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. mu-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Calpain / metabolism*
  • Cell Death / physiology
  • Cell Line
  • Cells, Cultured
  • Coculture Techniques
  • Dopamine / metabolism*
  • Female
  • Gliosis / physiopathology*
  • Male
  • Mesencephalon / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / physiology*
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Neurons / physiology*
  • Rats
  • Rats, Inbred F344
  • Superoxides / metabolism


  • Superoxides
  • NADPH Oxidases
  • Calpain
  • mu-calpain
  • Dopamine