BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity

Lambert, E.; Gelle, C.; Leclerc, V.; Freire-Regatillo, A.; Barois, N.; Malfoi, T.; Hermant, X.; Demiautte, F.; Lafont, F.; Amouyel, P.; Blary, K.; Kuenen, S.; Najdek, C.; Verstreken, P.; Siedlecki-Wullich, D.; Yger, P.; Lambert, J.-C.; Kilinc, D.; Dourlen, P.

doi:10.1101/2025.08.11.669624

bioRxiv · 10.1101/2025.08.11.669624

BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity

Lambert, E.·Gelle, C.·Leclerc, V.·Freire-Regatillo, A.·Barois, N.·Malfoi, T.·Hermant, X.·Demiautte, F.·Lafont, F.·Amouyel, P.·Blary, K.·Kuenen, S.·Najdek, C.·Verstreken, P.·Siedlecki-Wullich, D.·Yger, P.·Lambert, J.-C.·Kilinc, D.·Dourlen, P.

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Abstract

Alzheimers disease (AD) is characterized by a strong genetic predisposition and by an early loss of synaptic connectivity that strongly correlates with cognitive deficit. Some genetic determinants could contribute to synapse frailty toward AD pathology. However, the role of genetic determinants in AD pathogenesis remains poorly understood at the synaptic level. Here, we show that the expression of an isoform of the major AD susceptibility gene BIN1 in the presynaptic compartment results in synaptic loss. Using electrophysiology, we observed an early loss of synaptic transmission upon BIN1 isoform 1 (BIN1iso1) expression in Drosophila retinal photoreceptor neurons. This was not observed for the other human BIN1 isoforms tested, isoform 8 and isoform 9. Structural analysis of photoreceptor neuron synapses shows a strong accumulation of abnormally large vesicles in the presynaptic compartment, reminiscent of this same isoform-induced endosome defects in cell bodies. In addition, the expression of BIN1iso1 in motoneurons of the Drosophila neuromuscular junction alters the morphology of synaptic boutons, with a greater number and a smaller size of synaptic boutons, and the appearance of satellite boutons. As opposed to endosomal defects in cell body, modulating the Rab11 recycling endosome regulator did not prevent BIN1iso1 synaptotoxicity. To test if synaptic deficits are conserved in a mammalian model and to assert a presynaptic vs postsynaptic role for BIN1, we used rat primary neurons cultured in microfluidic devices that restrict gene expression modulation in particular neuron populations. We found a loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment, which was confirmed by microelectrode array analysis. Together, our results suggest that BIN1 expression in the presynaptic terminal, but not the postsynaptic terminal leads to an isoform-specific, deleterious effect on synaptic integrity. BIN1 synaptotoxicity could contribute to the synapse loss observed early in AD. This supports the idea that genetic determinants could make synapses prone to failure in AD.

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Lambert, E., Gelle, C., Leclerc, V., Freire-Regatillo, A., Barois, N., Malfoi, T., Hermant, X., Demiautte, F., Lafont, F., Amouyel, P., Blary, K., Kuenen, S., Najdek, C., Verstreken, P., Siedlecki-Wullich, D., Yger, P., Lambert, J.-C., Kilinc, D., Dourlen, P.. 2025-08-15. BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity. https://doi.org/10.1101/2025.08.11.669624

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