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000165261 1001_ $$aFrieg, Benedikt$$b0
000165261 245__ $$aQuaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein.
000165261 260__ $$aLondon$$bSpringer Nature$$c2022
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000165261 520__ $$aParkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases that are neuropathologically characterized by α-synuclein inclusions. Increasing evidence supports the aggregation of α-synuclein in specific brain areas early in the disease course, followed by the spreading of α-synuclein pathology to multiple brain regions. However, little is known about how the structure of α-synuclein fibrils influence its ability to seed endogenous α-synuclein in recipient cells. Here, we aggregated α-synuclein by seeding with homogenates of PD- and MSA-confirmed brain tissue, determined the resulting α-synuclein fibril structures by cryo-electron microscopy, and characterized their seeding potential in mouse primary oligodendroglial cultures. The combined analysis shows that the two patient material-amplified α-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface and their ability to recruit endogenous α-synuclein. Our study indicates that the quaternary structure of α-synuclein fibrils modulates the seeding of α-synuclein pathology inside recipient cells. It thus provides an important advance in the quest to understand the connection between the structure of α-synuclein fibrils, cellular seeding/spreading, and ultimately the clinical manifestations of different synucleinopathies.
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000165261 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000165261 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000165261 650_2 $$2MeSH$$aAnimals
000165261 650_2 $$2MeSH$$aCryoelectron Microscopy
000165261 650_2 $$2MeSH$$aMice
000165261 650_2 $$2MeSH$$aMultiple System Atrophy: pathology
000165261 650_2 $$2MeSH$$aParkinson Disease
000165261 650_2 $$2MeSH$$aSynucleinopathies
000165261 650_2 $$2MeSH$$aalpha-Synuclein: chemistry
000165261 7001_ $$00000-0003-3378-0683$$aGeraets, James A$$b1
000165261 7001_ $$0P:(DE-2719)2812850$$aStrohäker, Timo$$b2$$udzne
000165261 7001_ $$00000-0002-2172-5110$$aDienemann, Christian$$b3
000165261 7001_ $$aMavroeidi, Panagiota$$b4
000165261 7001_ $$00000-0003-0732-0122$$aJung, Byung Chul$$b5
000165261 7001_ $$00000-0002-4707-933X$$aKim, Woojin S$$b6
000165261 7001_ $$aLee, Seung-Jae$$b7
000165261 7001_ $$aXilouri, Maria$$b8
000165261 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b9$$udzne
000165261 7001_ $$00000-0003-1803-5431$$aSchröder, Gunnar F$$b10
000165261 773__ $$0PERI:(DE-600)2919698-X$$a10.1038/s42003-022-03948-y$$gVol. 5, no. 1, p. 1040$$n1$$p1040$$tCommunications biology$$v5$$x2399-3642$$y2022
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