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001     165354
005     20240301164619.0
024 7 _ |a 10.3233/JPD-223516
|2 doi
024 7 _ |a pmid:36278361
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024 7 _ |a 1877-7171
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024 7 _ |a 1877-718X
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024 7 _ |a altmetric:137623223
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037 _ _ |a DZNE-2022-01631
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Brás, Inês C
|b 0
245 _ _ |a Molecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity.
260 _ _ |a Amsterdam
|c 2022
|b IOS Press
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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650 _ 7 |a Alpha-synuclein
|2 Other
650 _ 7 |a Tau
|2 Other
650 _ 7 |a extracellular vesicles
|2 Other
650 _ 7 |a huntingtin
|2 Other
650 _ 7 |a neuronal function
|2 Other
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Exosomes: metabolism
|2 MeSH
650 _ 2 |a Protein Transport
|2 MeSH
700 1 _ |a Khani, Mohammad H
|b 1
700 1 _ |a Vasili, Eftychia
|b 2
700 1 _ |a Möbius, Wiebke
|b 3
700 1 _ |a Riedel, Dietmar
|b 4
700 1 _ |a Parfentev, Iwan
|b 5
700 1 _ |a Gerhardt, Ellen
|b 6
700 1 _ |a Fahlbusch, Christiane
|b 7
700 1 _ |a Urlaub, Henning
|b 8
700 1 _ |a Zweckstetter, Markus
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700 1 _ |a Gollisch, Tim
|b 10
700 1 _ |a Outeiro, Tiago F
|0 P:(DE-2719)2814138
|b 11
|e Last author
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773 _ _ |a 10.3233/JPD-223516
|g p. 1 - 26
|0 PERI:(DE-600)2599550-9
|n 8
|p 2397 - 2422
|t Journal of Parkinson's Disease
|v 12
|y 2022
|x 1877-7171
856 4 _ |u https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd223516
856 4 _ |u https://pub.dzne.de/record/165354/files/DZNE-2022-01631_Restricted.pdf
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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