title: Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons.
abstract: Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD). However, factors mediating microglial activation in PD are poorly understood. Proinflammatory cytokines, such as interferon-gamma (IFN-gamma), orchestrate the actions of microglia. We report here that PD patients express significantly elevated levels of IFN-gamma in their blood plasma. After this initial finding, we found that IFN-gamma-deficient mice displayed attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra pars compacta dopaminergic cell loss along with reduced loss of striatal tyrosine hydroxylase and dopamine transporter fiber density. MPTP-induced depletion of striatal dopamine and its metabolite DOPAC (3,4-dihydroxyphenylacetic acid), as well as deltaFosB, a marker of postsynaptic dysfunction, were also attenuated in these knock-out mice. Consistent with the role for IFN-gamma in microglial activation, MPTP-induced morphological activation of microglia was abrogated compared with wild-type mice. To examine more mechanistically the role of IFN-gamma in microglial activation, we evaluated the interactions between microglia and dopaminergic neurons in an in vitro mixed microglia/midbrain neuron rotenone-induced death paradigm. In this in vitro paradigm, dopaminergic neurons are selectively damaged by rotenone. Exogenous IFN-gamma ligand alone and without rotenone resulted in dopaminergic cell loss, but only in the presence of microglia. The addition of an IFN-gamma neutralizing antibody attenuated neuronal loss as a result of rotenone treatment. The presence of only wild-type microglia and not those deficient in IFN-gamma receptor elicited significant dopaminergic cell loss when exposed to rotenone. Neurons deficient in IFN-gamma receptor, however, did not display increased resistance to death. Finally, levels of IFN-gamma message increased in microglia in response to rotenone. Together, these data suggest that IFN-gamma participates in death of dopaminergic neurons by regulating microglial activity.
authors: Ottawa Health Research Institute, Neuroscience Group, Ottawa, Ontario, Canada K1H 8M5.
authors: Matthew P
authors: MP
authors: Mount
authors: Arman
authors: A
authors: Lira
authors: David
authors: D
authors: Grimes
authors: Patrice D
authors: PD
authors: Smith
authors: Sylvie
authors: S
authors: Faucher
authors: Ruth
authors: R
authors: Slack
authors: Hymie
authors: H
authors: Anisman
authors: Shawn
authors: S
authors: Hayley
authors: David S
authors: DS
authors: Park
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology
chemical_list: D007371:Interferon-gamma; D004298:Dopamine