Engineered proteins to restore and enhance neurotransmitter release
- 1Harvard Medical School
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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BibTeX
@misc{chin2026engineered,
title = {{Engineered proteins to restore and enhance neurotransmitter release}},
author = {M. Chin and K. Yang and R. C. Lopez and C. Tan and P. S. Kaeser},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.761409},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.761409v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Engineered proteins to restore and enhance neurotransmitter release
AU - M. Chin
AU - K. Yang
AU - R. C. Lopez
AU - C. Tan
AU - P. S. Kaeser
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.761409
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.761409v1
AB - 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.
ER -