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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Disease Models, Animal
  • Genetic Therapy
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Interferon-beta / therapeutic use
  • Lewy Body Disease / metabolism
  • Lewy Body Disease / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Parkinson Disease / therapy
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism*
  • Signal Transduction
  • Transcriptome
  • alpha-Synuclein / metabolism

Substances

  • Ifnar1 protein, mouse
  • alpha-Synuclein
  • Receptor, Interferon alpha-beta
  • Interferon-beta