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: 10861709
• 负责人: Ping-Yue Pan
• 金额: $ 0.42万
• 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/10861709
• 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 调节的突触传递对于维持大脑的正常功能至关重要， 突触基因通常与神经和神经变性疾病有关。该项目的目标是 揭示突触基因SYNJ 1（编码synaptojanin 1，synj 1）的分子和细胞机制， 导致基底神经节运动控制功能障碍。SYNJ 1中的错义突变（称为 PARK 20）与早发性非典型帕金森症有关。携带R258 Q疾病突变或 缺失SYNJ 1基因的一个拷贝（SYNJ 1 +/-）显示运动缺陷、受损的突触囊泡（SV）再循环 以及多巴胺能轴突和终末的营养不良性变化。然而，synj 1部分 功能丧失导致基底神经节中多巴胺能通路的功能障碍仍然不清楚。 Synj 1是一种在轴突末端富集的肌醇磷酸酶，在那里它调节SV再循环。我们 初步研究表明，SYNJ 1缺陷导致中脑特异性PIP 2改变，异常 突触前钙信号、SV循环受损和中脑神经元突触前终末增大。 我们推测SYNJ 1的缺失会导致重要信号脂质的失调，从而导致钙离子的异常。 通道功能，改变多巴胺释放和受损的膜运输。我们将深入开展 SYNJ 1缺陷小鼠和表达最近鉴定的SYNJ 1疾病的培养神经元的研究 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;免疫化学结合电子显微镜研究膜运输;和一种新的 光学多巴胺传感器结合生物化学和行为分析来检测多巴胺 传输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传导和共同信号传导的损伤 神经退行性疾病中其他突触基因共享的通路。本研究成果也有望获得 在synj 1介导的细胞类型特异性调节的见解，并提供新的治疗方法的新的前景。

项目成果

Mini-review: Synaptojanin 1 and its implications in membrane trafficking.

• DOI: 10.1016/j.neulet.2021.136288
• 发表时间: 2021-11-20
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Choudhry H;Aggarwal M;Pan PY
• 通讯作者: Pan PY

Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes.

Synaptojanin1 缺陷会上调星形胶质细胞中基础自噬体的形成。

• DOI: 10.1016/j.jbc.2021.100873
• 发表时间: 2021-07
• 期刊: The Journal of biological chemistry
• 作者: Pan PY;Zhu J;Rizvi A;Zhu X;Tanaka H;Dreyfus CF
• 通讯作者: Dreyfus CF

Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter.

帕金森病基因 Synaptojanin1 会失调多巴胺转运蛋白的表面维持。

• DOI: 10.21203/rs.3.rs-4021466/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Saenz,Jacqueline;Khezerlou,Elnaz;Aggarwal,Meha;Shaikh,Amina;Ganti,Naga;Herborg,Freja;Pan,Ping-Yue
• 通讯作者: Pan,Ping-Yue

Cocaine-regulated trafficking of dopamine transporters in cultured neurons revealed by a pH sensitive reporter.

• DOI: 10.1016/j.isci.2022.105782
• 发表时间: 2023-01-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Saenz, Jacqueline;Yao, Oscar;Khezerlou, Elnaz;Aggarwal, Meha;Zhou, Xiaofeng;Barker, David J.;DiCicco-Bloom, Emanuel;Pan, Ping-Yue
• 通讯作者: Pan, Ping-Yue