Role of PS1 in neurodegeneration

PS1 在神经退行性疾病中的作用

• 批准号: 8847619
• 负责人: OKSANA BEREZOVSKA
• 金额: $ 48.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847619
• 关键词: Active Sites; Adopted; Affect; Age; Aging; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Area; Binding; Biochemical; Biological; Brain; Calcium; Cells; Chemicals; Chronic; Cleaved cell; Clip; Complex; Data; Disease; Electric Stimulation; Endocytosis; Event; Exocytosis; Functional disorder; Generations; Health; Healthcare; Hippocampus (Brain); Human; Individual; Length; Life; Light; Link; Measurement; Microfilaments; Molecular Conformation; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optics; Pathogenesis; Pathology; Peptides; Phosphorylation; Phosphotransferases; Physiological; Population; Presynaptic Terminals; Production; Proteins; Proteomics; Public Health; Regulation; Reporting; Rhodopsin; Role; Site; Slice; Stimulus; Synapses; Synapsins; Synaptic Vesicles; Synaptosomes; Techniques; Testing; Therapeutic; Translating; aged; aging brain; amyloid precursor protein processing; cellular imaging; functional outcomes; in vivo; inhibitor/antagonist; kinase inhibitor; mutant; neurotoxic; neurotransmitter release; novel; novel therapeutics; presenilin-1; prevent; research study; response; secretase; sensor; synaptic function; synaptotagmin I

DESCRIPTION (provided by applicant): Synaptic dysfunction and Aß accumulation are the key features of Alzheimer's disease (AD) pathology. Numerous studies have shown that Aß can be produced in activity-dependent manner, and this correlates with synaptic vesicle exocytosis. PS1/g-secretase is present at the synaptic terminals, and our preliminary data show that it changes its conformation rapidly and reversibly in concert with synaptic activity and calcium (Ca2+) influx. Presenilin 1 (PS1) is the catalytic component of γ-secretase, which liberates the C-terminus of Aß peptide, and thus determines both amount of Aß and which Aß species will be produced: Aß40 or the longer, highly fibrillogenic and neurotoxic Aß42. However, the cell biological mechanisms that control precision of the PS1/γ-secretase cleavage site and local Aß production at the synapse remains unknown. PS1 phosphorylation by several kinases has been reported; however mechanistic effect of the PS1 phosphorylation remains unclear. Aim 1 will determine whether neuronal activity/Ca2+-induced phosphorylation of PS1/γ-secretase represents the regulatory mechanism of PS1 conformation and function at the synapse. Furthermore, our recent proteomics screen of mouse brain lysates in the presence or absence of calcium identified two novel PS1 interacting proteins, synapsin1 (Syn1) and synaptotagmin1 (Syt1), that showed strong but opposing Ca2+-dependent profiles of binding to PS1. Syn1 anchors synaptic vesicles to actin filaments, but releases them after Ca2+-induced Syn1 phosphorylation. Syt1 acts as Ca2+sensor in neurotransmitter release. Aim 2 will explore whether, Ca2+ influx may function as a switch controlling PS1 conformation and interactions with Syn1 and Syt1. In addition, we will test if PS1 interactions with Syn1 and Syt1 modulate PS1/γ-secretase and APP processing at the synapse in an activity-controlled manner. Aim 3 will validate physiological relevance of the newly found PS1 interaction with synaptic proteins in vivo by establishing if it is affected in aged and/or diseased brain, and whether these interactions can be manipulated pharmacologically. This study will provide mechanistic data for PS1 conformational changes, will explore novel PS1 interactions with synaptic vesicle machinery proteins, and will elucidate novel Aß-dependent and independent role of PS1 at the synapse. Understanding these issues is of high importance because manipulation of the PS1 conformation and synaptic interactions may translate into novel therapeutic strategies.

描述（由申请人提供）：突触功能障碍和 Aß 积累是阿尔茨海默病 (AD) 病理学的关键特征。大量研究表明，Aß 可以以活性依赖性方式产生，这与突触小泡 PS1/g 的胞吐作用相关。 -分泌酶存在于突触末端，我们的初步数据表明，它与突触活动和钙一致，快速且可逆地改变其构象(Ca2+) 流入早老素 1 (PS1) 是 γ-分泌酶的催化成分，可释放 Aß 肽的 C 末端，从而决定 Aß 的量以及将产生哪种 Aß：Aß40 或更长、高度高的 Aß。然而，控制 PS1/γ-分泌酶裂解位点和局部精度的细胞生物学机制。几种激酶对 PS1 的磷酸化作用尚不清楚；然而，PS1 磷酸化的机制仍不清楚，目的 1 将决定神经元活动/Ca2+ 诱导的 PS1/γ-分泌酶磷酸化是否代表了 PS1/γ-分泌酶的调节机制。此外，我们最近对存在或不存在钙的小鼠大脑裂解物进行的蛋白质组学筛选发现了两种新型 PS1 相互作用蛋白， synapsin1 (Syn1) 和 synaptotagmin1 (Syt1) 与 PS1 的结合表现出强烈但相反的 Ca2+ 依赖性特征，将突触小泡锚定在肌动蛋白丝上，但在 Ca2+ 诱导的 Syn1 磷酸化后释放它们，充当神经递质中的 Ca2+ 传感器。发布的目标 2 将探讨 Ca2+ 流入是否可以作为控制 PS1 构象的开关。此外，我们将测试 PS1 与 Syn1 和 Syt1 的相互作用是否以活动控制的方式调节突触处的 PS1/γ-分泌酶和 APP 处理，目的 3 将验证新发现的 PS1 的生理相关性。通过确定突触蛋白在衰老和/或患病大脑中是否受到影响，以及这些相互作用是否可以通过药理学来操纵，本研究将为 PS1 构象变化提供机制数据，并将进行探索。新的 PS1 与突触小泡机械蛋白的相互作用，并将阐明 PS1 在突触中新的 Aß 依赖性和独立作用。理解这些问题非常重要，因为对 PS1 构象和突触相互作用的操纵可能转化为新的治疗策略。