title: Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity.
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. 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.
authors.affiliation: Department of Anatomy & Neurobiology, Sanger Hall, Room 9-048, 1101 E. Marshall Street, Virginia Commonwealth University Medical Campus, Box 980709, Richmond, VA 23298-0709, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Levesque
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.forename: Vincent
authors.initials: V
authors.lastname: Gregoria
authors.forename: Laura B
authors.initials: LB
authors.lastname: Thorpe
authors.forename: Shannon
authors.initials: S
authors.lastname: Dallas
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Polikov
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005911:Gliosis / Q000503:physiopathology*; D008297:Male; D008636:Mesencephalon / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D019255:NADPH Oxidases; D002154:Calpain; C449002:mu-calpain; D004298:Dopamine