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Cell. 2015 Oct 8;163(2):324-39. doi: 10.1016/j.cell.2015.08.069.

Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.

Author information

  • 1Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 2Department of Clinical Sciences, Lund University, 22100 Lund, Sweden.
  • 3Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, 2200 Copenhagen, Denmark.
  • 4Institute for Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
  • 5Department of Neurology, University of Freiburg, 79106 Freiburg, Germany.
  • 6Institute for Neuropathology, University of Freiburg, 79106 Freiburg, Germany; Centre for Biological Signaling Studies, University of Freiburg, 79106 Freiburg, Germany.
  • 7Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, UK.
  • 8Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: shohreh.issazadeh@bric.ku.dk.

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMID:
26451483
[PubMed - indexed for MEDLINE]
PMCID:
PMC4601085
Free PMC Article
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