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

被引：185

作者：

Ejlerskov, Patrick ^{[1
]}

Hultberg, Jeanette Goransdotter ^{[1
]}

Wang, JunYang ^{[1
]}

Carlsson, Robert ^{[1
]}

Ambjorn, Malene ^{[1
]}

Kuss, Martin ^{[1
]}

Liu, Yawei ^{[1
]}

Porcu, Giovanna ^{[1
]}

Kolkova, Kateryna ^{[1
]}

Rundsten, Carsten Friis ^{[1
]}

Ruscher, Karsten ^{[2
]}

Pakkenberg, Bente ^{[3
]}

Goldmann, Tobias ^{[4
]}

Loreth, Desiree ^{[5
]}

Prinz, Marco ^{[4
,6
]}

Rubinsztein, David C. ^{[7
]}

Issazadeh-Navikas, Shohreh ^{[1
]}

机构：

[1] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark

[2] Lund Univ, Dept Clin Sci, S-22100 Lund, Sweden

[3] Bispebjerg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark

[4] Univ Freiburg, Inst Neuropathol, D-79106 Freiburg, Germany

[5] Univ Freiburg, Dept Neurol, D-79106 Freiburg, Germany

[6] Univ Freiburg, Ctr Biol Signaling Studies, D-79106 Freiburg, Germany

[7] Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England

来源：

CELL | 2015年 / 163卷 / 02期

关键词：

CENTRAL-NERVOUS-SYSTEM; ALPHA-SYNUCLEIN; INTERFERON-BETA; IN-VIVO; ALZHEIMERS-DISEASE; CELLS; MICE; DOPAMINE; BRAIN; DYSFUNCTION;

D O I：

10.1016/j.cell.2015.08.069

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-beta (IFN-beta) 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 alpha-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-beta signaling caused defects in neuronal autophagy prior to alpha-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-beta promoted neurite growth and branching, autophagy flux, and alpha-synuclein degradation in neurons. In addition, lentiviral IFN-beta overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-beta in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.

引用

页码：324 / 339

页数：16

共 44 条

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