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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Alpha synuclein (aSyn) is abundant in the brain and strongly implicated in Parkinson’s disease (PD), genetically and through its accumulation in neuronal pathognomonic inclusions. While mutations or increased expression of wild-type aSyn can cause familial PD, it remains unclear whether increased aSyn alone impairs presynaptic function. Here, we overexpressed human aSyn (haSyn) in rodent glutamatergic neurons and analysed presynaptic function. Expression levels mimicked SNCA gene triplications, as seen in certain familial forms of PD. In continental cultures, haSyn overexpression was not toxic nor did it alter the levels of presynaptic SNAP-25 or postsynaptic PSD-95. Analyses of autaptic neurons revealed no significant differences in evoked or spontaneous neurotransmission release, nor in synaptic plasticity. These results indicate that rodent glutamatergic neurons are resilient to aSyn overexpression. Our findings suggest neurotoxicity associated with aSyn overexpression is not universal, and that a deeper understanding of aSyn biology and pathobiology is necessary.
Author(s): Santos PI, Garcia-Plaza IH, Shaib A, Rhee JS, Chouaib AA, Brose N, Rizzoli SO, Daniel J, Outeiro TF
Publication type: Article
Publication status: Published
Journal: npj Parkinson's Disease
Year: 2025
Volume: 11
Issue: 1
Online publication date: 12/08/2025
Acceptance date: 19/07/2025
Date deposited: 02/09/2025
ISSN (electronic): 2373-8057
Publisher: Nature Research
URL: https://doi.org/10.1038/s41531-025-01085-x
DOI: 10.1038/s41531-025-01085-x
Data Access Statement: The datasets generated and/or analysed during the current study are available from the corresponding authors on request. The in-house written scripts in IJ1 and Java language for Fiji and ImageJ (NIH) generated and used to analyse synaptic proteins are available from GitHub (https://github. com/AbedChouaib/Synapse-Count).
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