title: Type-1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease.
abstract: Type-1 interferons (IFNs) are pleiotropic cytokines with a critical role in the initiation and regulation of the pro-inflammatory response. However, the contribution of the type-1 IFNs to CNS disorders, specifically chronic neuropathologies such as Parkinson's disease is still unknown. Here, we report increased type-1 IFN signaling in both post mortem human Parkinson's disease samples and in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. In response to MPTP, mice lacking the type-1 IFN receptor (IFNAR1(-/-) ) displayed decreased type-1 IFN signaling, an attenuated pro-inflammatory response and reduced loss of dopaminergic neurons. The neuroprotective potential of targeting the type-1 IFN pathway was confirmed by reduced neuroinflammation and DA cell death in mice treated with a blocking monoclonal IFNAR1 (MAR-1) antibody. The MPTP/MAR-1 treated mice also displayed increased striatal dopamine levels and improved behavioural outcomes compared to their MPTP/IgG controls. These data, implicate for the first time, a deleterious role for the type-1 IFNs as key modulators of the early neuroinflammatory response and therefore the neuronal cell death in Parkinson's disease. GLIA 2016;64:1590-1604.
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Bevan S
authors.initials: BS
authors.lastname: Main
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Moses
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Brody
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, 3010, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Frugier
authors.affiliation: Monash Biomedical Proteomics Facility, Monash University, Clayton, 3800, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Steer
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, 3010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crack
authors.affiliation: Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.
authors.forename: Juliet M
authors.identifier: 0000-0002-4596-6760
authors.initials: JM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D013378:Substantia Nigra / Q000473:pathology
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D004298:Dopamine
keywords: MPTP; Parkinson's disease; interferons; microglia; neuroinflammation