Transmitted alpha-synuclein extracellular vesicles downregulate axonal flux of retrograde carriers in recipient neurons

Duda, B. E.; Saber, S. H.; Lanoue, V.; Bademosi, A. T.; Gormal, R. S.; Wallis, T.; McCann, A. J.; Abosnwber, Y.; Cooper-White, J. J.; Verstreken, P.; Meunier, F. A.

doi:10.1101/2025.09.22.677685

bioRxiv · 10.1101/2025.09.22.677685

Transmitted alpha-synuclein extracellular vesicles downregulate axonal flux of retrograde carriers in recipient neurons

Duda, B. E.·Saber, S. H.·Lanoue, V.·Bademosi, A. T.·Gormal, R. S.·Wallis, T.·McCann, A. J.·Abosnwber, Y.·Cooper-White, J. J.·Verstreken, P.·Meunier, F. A.

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Abstract

-Synuclein (-syn) is a cytosolic protein located in nerve terminals and is involved in several neurodegenerative diseases such as Parkinsons disease. Recent studies have demonstrated that -syn can be transmitted from neuron to neuron via exosomal release, thereby contributing to the propagation of -syn pathology. However, the mechanism by which -syn-containing exosomes perturb the function of recipient neurons is currently unknown. Retrograde axonal transport of carriers emanating from the presynapse is essential for neuronal survival. To determine the effect of transmitted -syn on neuronal retrograde trafficking, we used conditioned medium from -syn transfected "donor" hippocampal neurons, applied to naive (non-transfected) "recipient" neurons cultured in microfluidic chambers. Time-lapse imaging of retrograde carriers containing cholera toxin-B subunit (CTB) was then performed in these recipient neurons. Here, we show that conditioned medium from -synWT-GFP transfected donor neurons significantly downregulated the frequency of retrograde CTB carriers when applied to recipient neurons. This effect was abolished by (i) inhibiting endocytosis in recipient neurons, (ii) by blocking exosomal release from donor cells via an Hsp90-dependent mechanism, or (iii) by using conditioned medium from neurons transfected with a Parkinsons mutant (-synA30P-GFP). Whilst transmitted -syn-mEos2, -synA30P-mEos2 and mEos2 alone were detected in recipient neurons using single molecule imaging, interestingly, -synWT-mEos2 exhibited lower mobility, and periodic (190 nm) immobilisations along the axon. Our data suggest that the downregulation of vesicular trafficking by transmitted -syn does not rely on the specific release nor uptake of exosomal -syn but probably depends on its interaction with endogenous -syn following endocytosis in recipient neurons. The transmitted -syn containing extracellular vesicles therefore controls essential axonal trafficking in recipient neurons, an effect lost with the Parkinsons disease mutant -synA30P.

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Duda, B. E., Saber, S. H., Lanoue, V., Bademosi, A. T., Gormal, R. S., Wallis, T., McCann, A. J., Abosnwber, Y., Cooper-White, J. J., Verstreken, P., Meunier, F. A.. 2025-09-22. Transmitted alpha-synuclein extracellular vesicles downregulate axonal flux of retrograde carriers in recipient neurons. https://doi.org/10.1101/2025.09.22.677685

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