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

项目摘要 大脑中细胞之间的交流主要通过神经元细胞中的化学分泌发生。 突触前末梢，突触囊泡（SV）与质膜融合， 释放神经递质分子。这些膜融合事件是由关键因素严格控制和调节的 突触蛋白如神经元SNARE蛋白以及Munc 13 -1/SNARE-13，Munc 18 -1/SNARE-18， 复合蛋白和突触结合蛋白。Munc 13 -1是突触传递中每一步的主要枢纽。此外，委员会认为， 人β 13直系同源物中的突变与严重的神经和发育障碍有关。 重要的是，Munc 13 -1各种功能的机制在很大程度上是未知的。我们最近 在Munc 13 -1的C-末端鉴定了一个新的结构域，称为HC 2 M，其在SV中起作用。 对接/引发，并且该结构域中的突变对突触传递和神经传导具有破坏性影响。 模式生物C.优雅综合运用遗传学行为学影像学和 通过生物化学的方法，我们将研究β-13在驱动神经元SNARE组装中的作用， SV预充的关键第一步。这个项目将揭示一些持久的机械奥秘 潜在的突触传递

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.