Leveraging the genetics and biochemistry of UNC-13 to uncover mechanisms driving neurotransmitter secretion

点击翻译按钮获取中文摘要

PROJECT SUMMARY Communication between cells in the brain occurs predominantly via chemical secretion in neuronal specializations called presynaptic terminals where synaptic vesicles (SVs) fuse with the plasma membrane to release neurotransmitter molecules. These membrane fusion events are tightly controlled and modulated by key synaptic proteins such as the neuronal SNARE proteins as well as Munc13-1/UNC-13, Munc18-1/UNC-18, Complexin, and Synaptotagmin. Munc13-1 is major hub for every step in synaptic transmission. Moreover, mutations in the human UNC-13 ortholog are associated with severe neurological and developmental disorders. Importantly, the mechanisms underlying the various Munc13-1 functions are largely unknown. We recently characterized a novel domain at the C-terminus of Munc13-1 termed HC2M that plays a role in SV docking/priming, and mutations in this domain have a devastating impact on synaptic transmission and nervous system function in the model organism C. elegans. Using a combination of genetic, behavioral, imaging, and biochemical methods, we will investigate the role of UNC-13 in driving the assembly of the neuronal SNAREs, a critical first step in SV priming. This project will shed light on some of the enduring mechanistic mysteries underlying synaptic transmission.