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



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Ejlerskov, Patrick 
Hultberg, Jeanette Göransdotter 
Wang, JunYang 
Carlsson, Robert 
Ambjørn, Malene 


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.



Animals, Autophagy, Disease Models, Animal, Genetic Therapy, Interferon-beta, Lewy Body Disease, Mice, Mice, Inbred C57BL, Neurons, Parkinson Disease, Receptor, Interferon alpha-beta, Signal Transduction, Transcriptome, alpha-Synuclein

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Elsevier BV
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095317/Z/11/A)
Support to S.I.-N. was from Danish Council For Independent Research (DFF)-Medical Sciences, Alzheimer-forskningsfonden, Danish Multiple Sclerosis Society, Danish Cancer Society and Lundbeck Foundation. D.C.R. is a Wellcome Trust Principal Research Fellow.