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: 10631066
• 负责人: Ping-Yue Pan
• 金额: $ 34.68万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631066
• 关键词: Address; Affect; Axon; Basal Ganglia; Behavioral; Biochemical; Brain; Brain Diseases; Brain region; Calcium; Calcium Channel; Calcium Signaling; Clathrin; Corpus striatum structure; Data; Defect; Disease; Dopamine; Down Syndrome; Early Onset Alzheimer Disease; Electron Microscopy; Electrophysiology (science); Endocytosis; Endoplasmic Reticulum; Exocytosis; FRAP1 gene; Functional disorder; Genes; Goals; Heterozygote; Hippocampus; Homeostasis; Human; Immunochemistry; Impairment; Induced Mutation; Inositol; Investigation; Knowledge; Lead; Link; Lipids; Mediating; Membrane; Memory; Methods; Midbrain structure; Missense Mutation; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optical reporter; Optics; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Perinatal mortality demographics; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Point Mutation; Presynaptic Terminals; Process; Recycling; Regulation; Research; Role; SYNJ1 gene; Second Messenger Systems; Signal Pathway; Signal Transduction; Substantia nigra structure; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptic Vesicles; Testing; Variant; Work; age related; atypical parkinsonism; calcium indicator; cell type; dopaminergic neuron; early onset; inhibitory neuron; insight; loss of function; loss of function mutation; mitochondrial dysfunction; motor control; motor deficit; motor disorder; motor impairment; mutant; nervous system disorder; novel; novel therapeutics; overexpression; presynaptic; programs; receptor function; sensor; synaptic function; trafficking; transmission process; voltage

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. The goal of this project is 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. Mice carrying the R258Q disease mutation or missing one copy of the SYNJ1 gene (SYNJ1+/-) display motor deficits, impaired synaptic vesicle (SV) recycling and dystrophic changes in dopaminergic axons and terminals. However, the mechanism whereby synj1 partial loss-of-function results in the dysfunction of the dopaminergic pathway in the basal ganglia remains unclear. Synj1 is an inositol phosphatase enriched in the axonal terminals, where it regulates SV recycling. Our preliminary study suggested that SYNJ1 deficiency leads to midbrain-specific changes in PIP2, abnormal presynaptic calcium signals, impaired SV recycling and enlarged presynaptic terminals in the midbrain neurons. We hypothesize that loss of SYNJ1 dysregulates important signaling lipids, which results in aberrant calcium channel function, altered dopamine release and impaired membrane trafficking. We will carry out an in-depth investigation for SYNJ1 deficient mice and cultured neurons expressing recently identified SYNJ1 disease mutations. We will use genetically encoded calcium indicators and electrophysiology to analyze presynaptic calcium; immunochemistry combined with electron microscopy to investigate membrane trafficking; and a novel optical dopamine sensor in combination with biochemical and behavioral analyses to examine dopamine transmission. By implementing the proposed research plan, we aim to reveal key pathogenic processes responsible for the impairment of the dopaminergic signaling in the basal ganglia and common signaling pathways shared by other synaptic genes in neurodegeneration. The result of this study is also expected to gain insights in synj1-mediated cell type-specific regulation and provide new perspectives for novel therapeutics.

项目摘要 受调节的突触传播对于维持大脑的正确功能至关重要，而突变是 突触基因通常与神经和神经退行性疾病有关。这个项目的目标是 发现突触基因Synj1（编码Synaptojanin1，synj1）的分子和细胞机制， 导致基底神经节功能障碍以进行运动控制。 Synj1中的错义突变（称为 Park20）与早期发作的非典型帕金森主义有关。携带R258Q疾病突变或 缺少一份Synj1基因（Synj1 +/-）的副本显示运动缺陷，突触囊泡（SV）回收受损 多巴胺能轴突和末端的营养不良变化。但是，Synj1部分的机制 功能丧失导致基底神经节多巴胺能途径的功能障碍尚不清楚。 Synj1是一种富含轴突末端的肌醇磷酸酶，它调节SV回收。我们的 初步研究表明，Synj1缺乏导致PIP2中脑特异性变化，异常 突触前钙信号，SV回收受损和中脑神经元中突触前末端的扩大。 我们假设Synj1的损失失调会导致钙异常 通道功能，多巴胺释放改变和膜运输受损。我们将进行深入 对Synj1缺乏小鼠和表达的培养神经元的研究最近发现了Synj1疾病 突变。我们将使用遗传编码的钙指标和电生理学来分析突触前 钙;免疫化学与电子显微镜相结合以研究膜运输；和一本小说 光学多巴胺传感器与生化和行为分析相结合以检查多巴胺 传播。通过实施拟议的研究计划，我们旨在揭示关键的致病过程 负责基底神经节中多巴胺能信号的损害和公共信号传导 神经变性中其他突触基因共享的途径。这项研究的结果也有望获得 Synj1介导的细胞类型特异性调节的见解，并为新型治疗剂提供了新的观点。