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000165354 0247_ $$2doi$$a10.3233/JPD-223516
000165354 0247_ $$2pmid$$apmid:36278361
000165354 0247_ $$2ISSN$$a1877-7171
000165354 0247_ $$2ISSN$$a1877-718X
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000165354 037__ $$aDZNE-2022-01631
000165354 041__ $$aEnglish
000165354 082__ $$a610
000165354 1001_ $$aBrás, Inês C$$b0
000165354 245__ $$aMolecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity.
000165354 260__ $$aAmsterdam$$bIOS Press$$c2022
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000165354 520__ $$aVarious cellular pathways have been implicated in the transfer of disease-related proteins between cells, contributing to disease progression and neurodegeneration. However, the overall effects of protein transfer are still unclear.Here, we performed a systematic comparison of basic molecular mechanisms involved in the release of alpha-synuclein, Tau, and huntingtin, and evaluated functional effects upon internalization by receiving cells.Evaluation of protein release to the extracellular space in a free form and in extracellular vesicles using an optimized ultracentrifugation protocol. The extracellular effects of the proteins and extracellular vesicles in primary neuronal cultures were assessed using multi-channel electrophysiological recordings combined with a customized spike sorting framework.We demonstrate cells differentially release free-forms of each protein to the extracellular space. Importantly, neuronal activity is distinctly modulated upon protein internalization in primary cortical cultures. In addition, these disease-related proteins also occur in extracellular vesicles, and are enriched in ectosomes. Internalization of ectosomes and exosomes by primary microglial or astrocytic cells elicits the production of pro-inflammatory cytokines, and modifies spontaneous electrical activity in neurons.Overall, our study demonstrates that released proteins can have detrimental effects for surrounding cells, and suggests protein release pathways may be exploited as therapeutic targets in different neurodegenerative diseases.
000165354 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000165354 650_7 $$2Other$$aAlpha-synuclein
000165354 650_7 $$2Other$$aTau
000165354 650_7 $$2Other$$aextracellular vesicles
000165354 650_7 $$2Other$$ahuntingtin
000165354 650_7 $$2Other$$aneuronal function
000165354 650_2 $$2MeSH$$aHumans
000165354 650_2 $$2MeSH$$aParkinson Disease: metabolism
000165354 650_2 $$2MeSH$$aNeurons: metabolism
000165354 650_2 $$2MeSH$$aExosomes: metabolism
000165354 650_2 $$2MeSH$$aProtein Transport
000165354 7001_ $$aKhani, Mohammad H$$b1
000165354 7001_ $$aVasili, Eftychia$$b2
000165354 7001_ $$aMöbius, Wiebke$$b3
000165354 7001_ $$aRiedel, Dietmar$$b4
000165354 7001_ $$aParfentev, Iwan$$b5
000165354 7001_ $$aGerhardt, Ellen$$b6
000165354 7001_ $$aFahlbusch, Christiane$$b7
000165354 7001_ $$aUrlaub, Henning$$b8
000165354 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b9$$udzne
000165354 7001_ $$aGollisch, Tim$$b10
000165354 7001_ $$0P:(DE-2719)2814138$$aOuteiro, Tiago F$$b11$$eLast author$$udzne
000165354 773__ $$0PERI:(DE-600)2599550-9$$a10.3233/JPD-223516$$gp. 1 - 26$$n8$$p2397 - 2422$$tJournal of Parkinson's Disease$$v12$$x1877-7171$$y2022
000165354 8564_ $$uhttps://content.iospress.com/articles/journal-of-parkinsons-disease/jpd223516
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