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

Patrick Ejlerskov; Jeanette Göransdotter Hultberg; JunYang Wang; Robert Carlsson; Malene Ambjørn; Martin Kuss; Yawei Liu; Giovanna Porcu; Kateryna Kolkova; Carsten Friis Rundsten; Karsten Ruscher; Bente Pakkenberg; Tobias Goldmann; Desiree Loreth; Marco Prinz; David C Rubinsztein; Shohreh Issazadeh-Navikas

doi:10.1016/j.cell.2015.08.069

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

Patrick Ejlerskov, Jeanette Göransdotter Hultberg, JunYang Wang, Robert Carlsson, Malene Ambjørn, Martin Kuss, Yawei Liu, Giovanna Porcu, Kateryna Kolkova, Carsten Friis Rundsten, Karsten Ruscher, Bente Pakkenberg, Tobias Goldmann, Desiree Loreth, Marco Prinz, David C Rubinsztein, Shohreh Issazadeh-Navikas

Department of Clinical Medicine

90 Citations (Scopus)

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.

Original language	English
Journal	Cell
Volume	163
Issue number	2
Pages (from-to)	324-39
Number of pages	16
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2015.08.069
Publication status	Published - 8 Oct 2015

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Ejlerskov, P., Hultberg, J. G., Wang, J., Carlsson, R., Ambjørn, M., Kuss, M., Liu, Y., Porcu, G., Kolkova, K., Friis Rundsten, C., Ruscher, K., Pakkenberg, B., Goldmann, T., Loreth, D., Prinz, M., Rubinsztein, D. C., & Issazadeh-Navikas, S. (2015). Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia. Cell, 163(2), 324-39. https://doi.org/10.1016/j.cell.2015.08.069

Ejlerskov, P, Hultberg, JG, Wang, J, Carlsson, R, Ambjørn, M, Kuss, M, Liu, Y, Porcu, G, Kolkova, K, Friis Rundsten, C, Ruscher, K, Pakkenberg, B, Goldmann, T, Loreth, D, Prinz, M, Rubinsztein, DC & Issazadeh-Navikas, S 2015, 'Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia', Cell, vol. 163, no. 2, pp. 324-39. https://doi.org/10.1016/j.cell.2015.08.069

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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.",

author = "Patrick Ejlerskov and Hultberg, {Jeanette G{\"o}ransdotter} and JunYang Wang and Robert Carlsson and Malene Ambj{\o}rn and Martin Kuss and Yawei Liu and Giovanna Porcu and Kateryna Kolkova and {Friis Rundsten}, Carsten and Karsten Ruscher and Bente Pakkenberg and Tobias Goldmann and Desiree Loreth and Marco Prinz and Rubinsztein, {David C} and Shohreh Issazadeh-Navikas",

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AU - Ejlerskov, Patrick

AU - Hultberg, Jeanette Göransdotter

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AU - Carlsson, Robert

AU - Ambjørn, Malene

AU - Kuss, Martin

AU - Liu, Yawei

AU - Porcu, Giovanna

AU - Kolkova, Kateryna

AU - Friis Rundsten, Carsten

AU - Ruscher, Karsten

AU - Pakkenberg, Bente

AU - Goldmann, Tobias

AU - Loreth, Desiree

AU - Prinz, Marco

AU - Rubinsztein, David C

AU - Issazadeh-Navikas, Shohreh

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N2 - 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.

AB - 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.

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JF - Cell

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

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