SYNJ1 Mediates a Novel Signaling Pathway in Parkinson's Disease

SYNJ1 介导帕金森病的新型信号通路

基本信息

批准号：
9150330
负责人：
Ping-Yue Pan
金额：
$ 21.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9150330
关键词：
Actins Age Alzheimer&apos s Disease Animal Model Arts Axon Base Composition Behavioral Binding Biological Assay Brain Brain Diseases Cell Survival Chromosomes Clathrin Confocal Microscopy Data Dendrites Disease Down Syndrome Endocytosis Family Gender Gene Expression Gene Mutation Genes Genetic Genetic study Goals Heterozygote Human Human Genetics In Vitro Inherited Inositol Intracellular Membranes Knockout Mice LRRK2 gene Link Lipids Measurement Mediating Membrane Lipids Membrane Protein Traffic Midbrain structure Modeling Monitor Morphology Mus Mutation Nerve Nerve Degeneration Neurites Neurons Optical reporter Optics PHluorin Parkinson Disease Parkinsonian Disorders Pathway interactions Perinatal Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipid Metabolism Phosphoric Monoester Hydrolases Phosphorylation Play Process Proteins Recessive Genes Recruitment Activity Regulation Reporting Role Signal Pathway Signal Transduction Staging Substantia nigra structure Synapses Synaptic Vesicles Testing Vertebral column alpha synuclein amphiphysin base behavioral outcome cell motility dopaminergic neuron early onset in vivo insight knock-down mouse model mutant nervous system disorder neurochemistry neurotoxicity novel novel therapeutics protein complex public health relevance synaptojanin tool trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): The goal of our project is to investigate pathogenic mechanism underlying Parkinson's disease (PD) based on inherited forms of PD. We and two other groups have identified the same mutation in SYNJ1 gene on chromosome 21q22 that is associated with early onset Parkinsonism. As one of the most important inositol phosphatases in the brain, synaptojanin1 (encoded by SYNJ1) is involved in many aspects of membrane trafficking and has been implicated in a number of brain disorders including Alzheimer's disease and Down's syndrome. However, its pathogenic mechanism in PD has not been studied. Emerging evidence reveals the convergence of pathogenic pathways for α-synuclein, LRRK2 and other PD-related genes in deregulating synaptic vesicle (SV) cycling in the early stage of PD. Our preliminary study shows shared phenotypes in SV endocytosis and dopaminergic transmission in SYNJ1 heterozygous mice and LRRK2-G2019S mice. SYNJ1 heterozygous mice develop abnormal dendritic morphology and lipid composition selectively in substantia nigra. Given that synaptojanin1 forms a protein complex with endophilin A, which was identified as a putative LRRK2 substrate, we propose a "LRRK2-endophilinA-synaptojanin1" signaling axis for the regulation of SV cycling, which is deregulated in PD. We will test the hypothesis using state-of-art optical tools and genetic animal models. Completion of our project is expected to provide insight into the pathogenic mechanism for PD and open new avenues for identification of novel therapeutics.

描述（由适用提供）：我们项目的目的是根据PD的遗传形式研究帕金森氏病（PD）的致病机制。我们和其他两个小组在21q22染色体上发现了与早期发作帕金森氏症相关的Synj1基因中的相同突变。作为大脑中最重要的肌醇磷酸酶之一，Synaptojanin1（由Synj1编码）参与了膜运输的许多方面，并且在包括阿尔茨海默氏病和唐氏综合症在内的许多脑部疾病中隐含了许多脑部疾病。但是，其PD中的致病机制尚未研究。新兴证据揭示了在PD的早期阶段，在过度调节突触囊泡（SV）循环的α-突触核蛋白，LRRK2和其他与PD相关基因的致病途径收敛。我们的初步研究表明，在Synj1杂合小鼠和LRRK2-G2019S小鼠中，SV内吞作用和多巴胺能传播中的共有表型。 Synj1杂合小鼠在黑质中有选择性地形成异常的树突状形态和脂质组成。鉴于Synaptojanin1与内菲林A形成蛋白质复合物，该蛋白质被确定为推定的LRRK2底物，我们建议用于调节SV循环的“ LRRK2-义磷酸 - 副硅酸盐信号轴”信号轴，该信号轴是在Pd中进行的。我们将使用最先进的光学工具和遗传动物模型检验假设。预计我们项目的完成将洞悉PD的致病机制和开放新途径，以鉴定新的治疗方法。