Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.

Ribe, E.; Ghosh, A.; Paslawski, W.; Savory, K. A.; Ballard, C.; Morin, P.; Cash, D.; Hirth, F.; Williams, G.; Svenningsson, P.; Aarsland, D.; Siow, R. C.; Killick, R.

doi:10.1101/2025.02.13.638131

bioRxiv · 10.1101/2025.02.13.638131

Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.

Ribe, E.·Ghosh, A.·Paslawski, W.·Savory, K. A.·Ballard, C.·Morin, P.·Cash, D.·Hirth, F.·Williams, G.·Svenningsson, P.·Aarsland, D.·Siow, R. C.·Killick, R.

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Abstract

It has been suggested that -synuclein (Syn), a major player in Parkinsons disease (PD), plays a role in Alzheimers disease (AD). Several reports have also concluded that Syn and amyloid-{beta} (A{beta}) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for A{beta}-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of Syn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of Syn (A53T-Syn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-Syn-driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-Syn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-Syn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates A{beta} synaptotoxicity. This indicates that A{beta} and Syn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD.

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Ribe, E., Ghosh, A., Paslawski, W., Savory, K. A., Ballard, C., Morin, P., Cash, D., Hirth, F., Williams, G., Svenningsson, P., Aarsland, D., Siow, R. C., Killick, R.. 2025-02-17. Synaptotoxic forms of amyloid-b and a-synuclein act through a common pathway.. https://doi.org/10.1101/2025.02.13.638131

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