Elucidating the Complexin C-terminal Domain Mechanism in Neurotransmission Regulation

阐明神经传递调节中的复合蛋白 C 末端结构域机制

基本信息

  • 批准号:
    10624237
  • 负责人:
  • 金额:
    $ 2.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-13 至 2023-10-12
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Elucidating the Complexin C-terminal domain mechanism in neurotransmission regulation Dysregulation of neurotransmission underlies the neuropathophysiology of conditions like Alzheimer’s, Parkisons Disease, amyotrophic lateral sclerosis, and autism. Synaptic vesicle (SV) fusion is a central process in neurotransmission and SNARE (Soluble NSF Attachment Protein Receptor) proteins are essential to SV fusion, but the regulatory proteins of SNAREs are key to understanding the mechanisms. Despite fantastic research progress since the discovery of SNAREs, the mechanistic details driving SV fusion remain elusive. Complexin (Cpx) is a regulator of SNAREs and localizes to SVs via a curvature-sensing motif in its C-terminal domain (CTD). Strikingly, Cpx is highly conserved in the animal kingdom – even simple multicellular organisms lacking bona fide synapse like Trichoplax have Cpx. C. elegans lends itself as an ideal model organism to study Cpx biology as the mammalian Cpx null mutation is lethal. Furthermore, C.elegans is easy to image and provides a powerful genetic tool with its origins as a genetics model organism. Variants of Cpx have been reported to be pathogenic for infantile myoclonic epilepsy and intellectual disability (Redler, S. et al. Eur J Hum Genet 2017). Specifically, the CTD was mutated and the inefficient localization of complexin is thought to result in disease. Our research plan investigates whether the CTD is functionally essential to complexin and which mechanisms the complexin CTD employs in localizing to synaptic vesicles. In Aim 1, I will explore the role of the CPX-1 CTD in recruitment to specific vesicle pools at the synapse and target the N-terminal half of CPX-1 with foreign tethers to bypass CTD membrane binding. In Aim 2, I will characterize the features of the CTD curvature sensor required for efficient SV targeting and explore potential biochemical interactions between CPX-1 and the SV protein RAB-3. I will also explore several genes identified in a forward genetic suppressor screen of cpx-1 to extend my search of potential CPX- 1 binding partners. These aims will combine genetic, molecular, imaging, and biochemical approaches to dissect and characterize a critical region of Cpx, providing answers to a long-standing question on the synaptic mechanisms of Cpx. Under this fellowship, I will have the opportunity to work with leading researchers at the Tri-Institutional campus (Weill Cornell, Rockefeller, and Memorial Sloan Kettering) conducting neuroscience and biophysical research in a collaborative and supportive environment. To expand my technical skills and knowledge, I will attend workshops, seminars, and conferences on topics important for my research. Research findings will be shared with the scientific community and public via conferences and publications.
项目摘要 复合蛋白C端结构域在神经传递调控中的作用机制 神经传递失调是阿尔茨海默氏症等疾病的神经病理生理学基础, 帕金森氏病、肌萎缩侧索硬化症和自闭症。突触囊泡(SV)融合是一个中心的 SNARE(可溶性NSF附着蛋白受体)蛋白是神经传递过程中必不可少的 SV融合,但SNARE的调节蛋白是理解机制的关键。尽管 自发现SNARE以来,令人惊叹的研究进展,驱动SV融合的机制细节 仍然难以捉摸复合蛋白(Complexin,Cpx)是SNARE的调节因子,通过曲率感应定位于SV 在其C-末端结构域(CTD)中的基序。令人惊讶的是,Cpx在动物王国中是高度保守的,即使是 缺乏真正突触简单的多细胞生物,如Trichoplax,具有Cpx。C.优雅的人 作为研究Cpx生物学的理想模式生物,因为哺乳动物Cpx无效突变是致命的。 此外,秀丽隐杆线虫很容易成像,并提供了一个强大的遗传工具,其起源是一个 遗传学模式生物 已报道Cpx的变体是婴儿肌阵挛性癫痫和智力障碍的致病性。 残疾(Redler,S.等人,Eur J Genet 2017)。具体来说,CTD发生突变, 复合蛋白的定位被认为导致疾病。我们的研究计划调查CTD是否 功能上对复合蛋白至关重要,以及复合蛋白CTD在定位于 突触囊泡在目标1中,我将探索CPX-1 CTD在特定囊泡库募集中的作用, 突触并靶向具有外源系链的CPX-1的N-末端一半以绕过CTD膜结合。在 目标2,我将描述有效SV定位所需CTD曲率传感器的特征, 探索CPX-1和SV蛋白RAB-3之间潜在的生物化学相互作用。我也将探索 在cpx-1的正向遗传抑制筛选中确定了几个基因,以扩展我对潜在CPX的搜索, 1绑定伙伴。这些目标将结合联合收割机的遗传,分子,成像和生物化学的方法 解剖和描述Cpx的关键区域,为长期存在的问题提供答案, Cpx的突触机制 在这个奖学金,我将有机会与领先的研究人员在三机构校园工作 (威尔康奈尔,洛克菲勒和纪念斯隆凯特林)进行神经科学和生物物理研究 在一个合作和支持的环境中。为了扩大我的技术技能和知识,我将参加 讲习班,研讨会和会议的主题对我的研究很重要。研究成果将被分享 通过会议和出版物与科学界和公众交流。

项目成果

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