title: Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.
abstract: Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ejlerskov
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jeanette Göransdotter
authors.initials: JG
authors.lastname: Hultberg
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: JunYang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Robert
authors.initials: R
authors.lastname: Carlsson
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Ambjørn
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuss
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Porcu
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Kolkova
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Friis Rundsten
authors.affiliation: Department of Clinical Sciences, Lund University, 22100 Lund, Sweden.
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, 2200 Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Pakkenberg
authors.affiliation: Institute for Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Department of Neurology, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Desiree
authors.initials: D
authors.lastname: Loreth
authors.affiliation: Institute for Neuropathology, University of Freiburg, 79106 Freiburg, Germany; Centre for Biological Signaling Studies, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: shohreh.issazadeh@bric.ku.dk.
authors.forename: Shohreh
authors.initials: S
authors.lastname: Issazadeh-Navikas
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D015316:Genetic Therapy; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C508032:Ifnar1 protein, mouse; D051844:alpha-Synuclein; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta