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: 9019606
• 负责人: Ping-Yue Pan
• 金额: $ 25.43万
• 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/9019606
• 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; 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; mouse model; mutant; myo-inositol-1 (or 4)-monophosphatase; 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(申请人提供)：我们的项目的目标是研究帕金森病(PD)的致病机制，基于帕金森病的遗传形式。我们和其他两个小组已经发现了染色体21q22上SYNJ1基因的相同突变，该突变与早发性帕金森综合征有关。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，并与阿尔茨海默病和唐氏综合症等许多大脑疾病有关。然而，其在帕金森病发病机制方面的研究尚不多见。新的证据显示，在PD的早期阶段，α-突触核蛋白、LRRK2和其他PD相关基因的致病途径在放松对突触小泡(SV)循环的调控中趋同。我们的初步研究表明，在SYNJ1杂合子小鼠和LRRK2-G2019S小鼠中，SV内吞和多巴胺能传递的表型是相同的。SYNJ1杂合子小鼠选择性地在黑质发育异常的树突形态和脂质成分。鉴于突触素1与内嗜素A形成蛋白质复合体，被认为是LRRK2底物，我们提出了一个“LRRK2-内嗜蛋白A-突触素1”信号轴来调节SV周期，这在PD中是不受调控的。我们将使用最先进的光学工具和遗传动物模型来验证这一假设。我们项目的完成有望为帕金森病的发病机制提供洞察力，并为识别新的治疗方法开辟新的途径。