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Molecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

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.

Publication metadata

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

Year: 2022

Volume: 12

Issue: 8

Pages: 2397-2422

Online publication date: 16/12/2022

Acceptance date: 28/09/2022

ISSN (print): 1877-7171

ISSN (electronic): 1877-718X

Publisher: IOS Press

URL: https://doi.org/10.3233/JPD-223516

DOI: 10.3233/JPD-223516

PubMed id: 36278361

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