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000155805 037__ $$aDZNE-2021-00965
000155805 041__ $$aEnglish
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000155805 1001_ $$0P:(DE-2719)9001519$$aGrozdanov, Veselin$$b0$$udzne
000155805 245__ $$aIncreased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease.
000155805 260__ $$aHoboken, NJ$$bWiley-Blackwell$$c2019
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000155805 520__ $$aExcessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α-synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α-synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α-synuclein by assessing cytokine release upon exposure.We show that pathologic α-synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation- dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α-synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α-synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α-synuclein. Furthermore, we demonstrate that α-synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.Taken together, our data suggest that α-synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α-synuclein. ANN NEUROL 2019;86:593-606.
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000155805 650_7 $$2NLM Chemicals$$aCytokines
000155805 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000155805 650_2 $$2MeSH$$aAnimals
000155805 650_2 $$2MeSH$$aCells, Cultured
000155805 650_2 $$2MeSH$$aCytokines: metabolism
000155805 650_2 $$2MeSH$$aExtracellular Vesicles: immunology
000155805 650_2 $$2MeSH$$aHumans
000155805 650_2 $$2MeSH$$aInflammation: complications
000155805 650_2 $$2MeSH$$aInflammation: metabolism
000155805 650_2 $$2MeSH$$aMice
000155805 650_2 $$2MeSH$$aMice, Transgenic
000155805 650_2 $$2MeSH$$aMicroglia: metabolism
000155805 650_2 $$2MeSH$$aMonocytes: metabolism
000155805 650_2 $$2MeSH$$aMutation
000155805 650_2 $$2MeSH$$aParkinson Disease: immunology
000155805 650_2 $$2MeSH$$aParkinson Disease: metabolism
000155805 650_2 $$2MeSH$$aalpha-Synuclein: adverse effects
000155805 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000155805 7001_ $$0P:(DE-HGF)0$$aBousset, Luc$$b1
000155805 7001_ $$0P:(DE-HGF)0$$aHoffmeister, Meike$$b2
000155805 7001_ $$0P:(DE-HGF)0$$aBliederhaeuser, Corinna$$b3
000155805 7001_ $$0P:(DE-HGF)0$$aMeier, Christoph$$b4
000155805 7001_ $$0P:(DE-HGF)0$$aMadiona, Karine$$b5
000155805 7001_ $$0P:(DE-HGF)0$$aPieri, Laura$$b6
000155805 7001_ $$0P:(DE-HGF)0$$aKiechle, Martin$$b7
000155805 7001_ $$0P:(DE-HGF)0$$aMcLean, Pamela J$$b8
000155805 7001_ $$0P:(DE-HGF)0$$aKassubek, Jan$$b9
000155805 7001_ $$0P:(DE-HGF)0$$aBehrends, Christian$$b10
000155805 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert$$b11$$udzne
000155805 7001_ $$0P:(DE-HGF)0$$aWeishaupt, Jochen H$$b12
000155805 7001_ $$0P:(DE-HGF)0$$aMelki, Ronald$$b13
000155805 7001_ $$0P:(DE-2719)9001513$$aDanzer, Karin M$$b14$$eLast author$$udzne
000155805 773__ $$0PERI:(DE-600)2037912-2$$a10.1002/ana.25557$$gVol. 86, no. 4, p. 593 - 606$$n4$$p593 - 606$$tAnnals of neurology$$v86$$x1531-8249$$y2019
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