The Role of SYNJ1 in Dysregulating the Basal Ganglia Function

项目摘要 受调节的突触传递对于维持大脑的正常功能是必不可少的，而基因突变 突触基因通常与神经和神经退行性疾病有关。在家长的资助中，我们 建议揭示突触基因SYNJ1(编码)的分子和细胞机制 Synaptojanin1，synj1)，在运动控制的基底节功能障碍中起作用。错义突变 在SYNJ1中(称为PARK20)与早发性非典型帕金森症有关，特征是 多巴胺能系统。然而，synj1部分功能丧失导致功能障碍的机制 基底节中的多巴胺能途径尚不清楚。我们假设SYNJ1的损失 调节重要的信号脂类，导致钙通道功能异常，膜受损 贩卖和改变多巴胺的释放。本增刊是专门为杰奎琳(杰姬)设计的 萨恩兹是一名研究生，种族背景较少，她的博士论文工作和职业生涯 发展。在研究SYNJ1如何调节多巴胺方面，它是对父母拨款中的目标3的补充 发信号。杰基将专注于分析多巴胺转运体的功能和细胞内运输 (DAT)与多巴胺信号有关。她将使用异种细胞以及我们新开发的神经元 开发条件性SYNJ1缺失小鼠以确定DAT内吞作用和活性受 Synj1的酶结构域及其下游的脂质信号通路。这项研究的完成将有所帮助 美国进一步了解synj1在DA信号中的作用，并使Jackie接触到广泛的尖端技术 为她未来的研究发展制定研究策略。

Project Summary Regulated synaptic transmission is essential in maintaining the proper function of the brain, and mutations in synaptic genes are often linked to neurological and neurodegenerative disorders. In the parent grant, we propose to uncover the molecular and cellular mechanisms of the synaptic gene, SYNJ1 (encoding synaptojanin1, synj1), in contributing to dysfunction of the basal ganglia for motor control. Missense mutations in SYNJ1 (known as PARK20) are associated with early-onset atypical Parkinsonism, featured by an impaired dopaminergic system. However, the mechanism whereby synj1 partial loss-of-function results in the dysfunction of the dopaminergic pathway in the basal ganglia remains unclear. We hypothesize that loss of SYNJ1 dysregulates important signaling lipids, which results in aberrant calcium channel function, impaired membrane trafficking and altered dopamine release. This supplement is developed specifically for Jacqueline (Jackie) Saenz, a graduate student with underrepresented ethnic background, for her PhD thesis work and career development. It is complimentary to the Aim 3 in the parent grant in investigating how SYNJ1 regulates dopamine signaling. Jackie will be focusing on analyzing the function and endocytic trafficking of the dopamine transporter (DAT) in relation to dopamine signaling. She will be using heterologous cells as well as neurons from our newly developed conditional SYNJ1 deletion mouse to determine that DAT endocytosis and activity are regulated by the enzymatic domains of synj1 and their downstream lipid signaling pathways. Completion of the study will help us further understand the role of synj1 in DA signaling and to expose Jackie to a wide range of cutting-edge research strategies for her future research development.