SYNJ1 Mediates a Novel Signaling Pathway in Parkinson's Disease

SYNJ1 介导帕金森病的新型信号通路

• 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
• 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' 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

 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（由申请人提供）：我们项目的目标是根据帕金森病的遗传形式研究帕金森病 (PD) 的致病机制。我们和其他两个小组在染色体 21q22 上的 SYNJ1 基因中发现了与早发性帕金森症相关的相同突变。作为大脑中最重要的肌醇磷酸酶之一，synaptojanin1（由 SYNJ1 编码）参与膜运输的许多方面，并与包括阿尔茨海默病和唐氏综合症在内的许多脑部疾病有关。但其在PD中的致病机制尚未被研究。新的证据揭示了 α-突触核蛋白、LRRK2 和其他 PD 相关基因的致病途径在 PD 早期对突触小泡 (SV) 循环的失调中的趋同。我们的初步研究显示 SYNJ1 杂合小鼠和 LRRK2-G2019S 小鼠的 SV 内吞作用和多巴胺能传递具有共同的表型。 SYNJ1杂合子小鼠在黑质中选择性地形成异常的树突形态和脂质组成。鉴于 synaptojanin1 与内亲蛋白 A 形成蛋白复合物，而内亲蛋白 A 被确定为推定的 LRRK2 底物，我们提出了一个“LRRK2-内亲蛋白 A-synaptojanin1”信号轴来调节 SV 循环，该信号在 PD 中失调。我们将使用最先进的光学工具和遗传动物模型来检验这一假设。我们项目的完成预计将深入了解帕金森病的致病机制，并为识别新疗法开辟新途径。