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Lookup NU author(s): Professor Tiago OuteiroORCiD
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BACKGROUND: Various 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. OBJECTIVE: 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.
Author(s): Bras IC, Khani MH, Vasili E, Mobius W, Riedel D, Parfentev I, Gerhardt E, Fahlbusch C, Urlaub H, Zweckstetter M, Gollisch T, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Journal of Parkinson's Disease
Online publication date: 16/12/2022
Acceptance date: 28/09/2022
ISSN (print): 1877-7171
ISSN (electronic): 1877-718X
Publisher: IOS Press
PubMed id: 36278361
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