Molecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity
2022 | journal article. A publication with affiliation to the University of Göttingen.
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Molecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity
Brás, I. C.; Khani, M. H. ; Vasili, E.; Möbius, W. ; Riedel, D. ; Parfentev, I. & Gerhardt, E. et al. (2022)
Journal of Parkinson's Disease, pp. 1-26. DOI: https://doi.org/10.3233/JPD-223516
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- Authors
- Brás, Inês C.; Khani, Mohammad H. ; Vasili, Eftychia; Möbius, Wiebke ; Riedel, Dietmar ; Parfentev, Iwan; Gerhardt, Ellen ; Fahlbusch, Christiane ; Urlaub, Henning ; Zweckstetter, Markus ; Outeiro, Tiago Fleming
- 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.
- Issue Date
- 2022
- Journal
- Journal of Parkinson's Disease
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1286: Quantitative Synaptologie
SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration - Organization
- Center for Biostructural Imaging of Neurodegeneration ; Universitätsmedizin Göttingen ; Klinik für Augenheilkunde ; Max-Planck-Institut für Experimentelle Medizin ; Max-Planck-Institut für Biophysikalische Chemie ; Institut für Klinische Chemie ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) ; Klinik für Neurologie ; Max-Planck-Institut für Multidisziplinäre Naturwissenschaften
- Working Group
- RG Gollisch (Sensory Processing in the Retina)
RG Möbius
RG Outeiro (Experimental Neurodegeneration)
RG Urlaub (Bioanalytische Massenspektrometrie) - ISSN
- 1877-7171
- eISSN
- 1877-718X
- Language
- English