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Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Dept Med, Toronto, ON, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada.ORCID iD: 0000-0001-5466-8370
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-9700-5419
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0001-7292-1608
2023 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 43, no 6, p. 3023-3035Article in journal (Refereed) Published
Abstract [en]

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

Place, publisher, year, edition, pages
Springer, 2023. Vol. 43, no 6, p. 3023-3035
Keywords [en]
Alpha-synuclein, SNARE, Proximity ligation assay, Synapse, Primary neurons
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-511391DOI: 10.1007/s10571-023-01355-3ISI: 000981547700001PubMedID: 37130995OAI: oai:DiVA.org:uu-511391DiVA, id: diva2:1799436
Funder
Swedish Research Council, 202102563Parkinsonfonden, 1405/2022The Swedish Brain Foundation, FO2022-0062Available from: 2023-09-22 Created: 2023-09-22 Last updated: 2023-09-22Bibliographically approved

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Ingelsson, MartinBergström, JoakimErlandsson, Anna

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