The Role of SYNJ1 in Dysregulating the Basal Ganglia Function

SYNJ1 在基底神经节功能失调中的作用

• 批准号: 10164973
• 负责人: Ping-Yue Pan
• 金额: $ 7.17万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164973
• 关键词: Basal Ganglia; Brain; Calcium Channel; Cells; Doctor of Philosophy; Dopamine; Endocytosis; Exposure to; Functional disorder; Genes; Impairment; Link; Lipids; Membrane; Missense Mutation; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neurons; Parkinsonian Disorders; Pathway interactions; Research; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic Transmission; System; Work; career development; dopamine transporter; early onset; graduate student; loss of function; motor control; nervous system disorder; parent grant; research and development; synaptojanin; trafficking

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.

项目概要 调节突触传递对于维持大脑的正常功能至关重要，而突变 突触基因通常与神经系统和神经退行性疾病有关。在家长补助金中，我们 提议揭示突触基因 SYNJ1（编码 synaptojanin1、synj1)，导致基底神经节运动控制功能障碍。错义突变 SYNJ1（称为 PARK20）中的基因与早发性非典型帕金森症相关，其特征是神经功能受损 多巴胺能系统。然而，synj1 部分功能丧失导致功能障碍的机制 基底神经节中多巴胺能通路的作用仍不清楚。我们假设 SYNJ1 丢失 重要的信号脂质失调，导致钙通道功能异常、膜受损 贩运和改变多巴胺释放。该补充剂专为杰奎琳（Jackie）开发 Saenz，一名少数族裔背景的研究生，因其博士论文工作和职业生涯 发展。它是对研究 SYNJ1 如何调节多巴胺的家长资助中的 Aim 3 的补充 发信号。 Jackie 将重点分析多巴胺转运蛋白的功能和内吞运输 （DAT）与多巴胺信号传导有关。她将使用异源细胞以及来自我们新的神经元 开发了条件性 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脂质信号通路。完成研究将有帮助 我们进一步了解 synj1 在 DA 信号传导中的作用，并使 Jackie 接触到广泛的前沿技术 她未来研究发展的研究策略。