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bioRxiv · 10.64898/2026.10.23.761409

Engineered proteins to restore and enhance neurotransmitter release

Chin, M.·Yang, K.·Lopez, R. C.·Tan, C.·Kaeser, P. S.
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Abstract

Synapse dysfunction is a hallmark feature of many neurological diseases. Synaptic transmission is initiated in nerve terminals, where active zone protein complexes control vesicle fusion for neurotransmitter release. Here, we engineer proteins that mediate active zone functions and demonstrate their use for reconstituting and strengthening neurotransmission. A protein composed of CaV{beta}4 and the RIM1 zinc finger, {beta}4-Zn, restored neurotransmitter release after active zone disruption through recruitment of Munc13. We develop {beta}4-MC, derived from the Munc13-1 MUN and C2C domains, which bypasses Munc13 recruitment and directly mediates vesicle docking, priming and fusion after active zone disruption. In {beta}4-MC, MUN domain functions are dispensable for docking, but active MUN and C2C domains are both necessary for neurotransmitter release. In wild-type mouse and human neurons, {beta}4-MC but not {beta}4-Zn strengthens neurotransmitter release. Furthermore, {beta}4-Zn and {beta}4-MC restore and enhance dopamine release in the mouse striatum, respectively. Hence, {beta}4 proteins are engineered secretory proteins with therapeutic potential as enhancers of synaptic function.

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Chin, M., Yang, K., Lopez, R. C., Tan, C., Kaeser, P. S.. 2026-10-24. Engineered proteins to restore and enhance neurotransmitter release. https://doi.org/10.64898/2026.10.23.761409

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