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Presenilin 1 Modulates Lysosome Function and Tau Degradation

Presenilin 1 调节溶酶体功能和 Tau 降解

基本信息

批准号：
10617810
负责人：
Carol Ann Deaton
金额：
$ 5.27万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10617810
关键词：
Address Affect Age of Onset Aging Alzheimer&apos s Disease Antibodies Autophagocytosis Autophagosome Axon BODIPY Binding Biology Catalytic Domain Cathepsins Cell membrane Characteristics Complex Data Defect Degradation Pathway Dendrites Endosomes Event Exhibits Functional disorder Genes Health Impairment Knowledge Light Lysosomes Measures Mediating Monitor Multivesicular Body Mutate Mutation Neurobiology Neurodegenerative Disorders Neurons Pathogenicity Pepstatins Peptide Hydrolases Peptides Play Process Production Proteins Proton Pump Rattus Recycling Reporting Role Supervision Swelling Synaptosomes Testing Vesicle Western Blotting autosome exosome extracellular familial Alzheimer disease gamma secretase human old age (65+)immunocytochemistry inhibitor innovation knock-down live cell imaging mutant optogenetics overexpression postsynaptic presenilin-1 presynaptic proteostasis secretase small hairpin RNA tau Proteins tau aggregation tau expression tau-1 trafficking vector

项目摘要

A common feature of Alzheimer’s disease (AD), as well as other older age onset neurodegenerative diseases, is the accumulation of misfolded, abnormally modified proteins. In AD, aggregates of tau are a classical hallmark. A significant contributing factor to the formation of these proteinaceous accumulations is dysfunction of the lysosome-dependent degradative pathways. Interestingly, the majority of autosomal dominant familial AD (FAD) cases are caused by mutations in presenilin 1 (PS1), the catalytic subunit of the  secretase complex, which also likely facilitates lysosomal function. However, the role of PS1 in mediating lysosome biology and the clearance of tau has not been fully delineated. Given previous studies and our preliminary data, the UNDERLYING PREMISE of this proposal is that in neurons PS1 plays a fundamental role in regulating the function of lysosomes and, thus, tau turnover. Lysosomes play a key role in maintaining proteostasis as multiple degradative pathways direct their cargos to the lysosome for degradation/recycling. Alterations in the activity or intracellular localization of lysosomes contribute to the pathogenic processes of these neurodegenerative diseases. Given the importance of lysosome function to neuron health, understanding how PS1 impacts lysosome biology is of high importance. CRITICAL KNOWLEDGE GAPS include: how depletion of PS1 in primary neurons impacts lysosome pH, the effects of PS1 depletion on autophagosome-lysosome and endosome-lysosome fusion, the impact of PS1 depletion on tau turnover and how re-acidification of lysosomes in neurons with PS1 depleted affects the PS1-induced lysosomal fusion defects and deficiencies in tau turnover. Considering these critical knowledge gaps the OVERALL HYPOTHESIS is that depletion of PS1 leads to impairment of lysosome function, localization and fusion events, which negatively impact tau clearance. In the context of this overall hypothesis, the specific aims of this proposal are to test the hypotheses: (1) that PS1 plays a role in the acidification, activity, and localization of lysosomes and other degradative vesicles within different neuronal compartments and (2) that vesicle- mediated processing/clearance and intraneuronal localization of tau is impaired by knockdown of PS1. These studies will be carried out using primary rat cortical neuron cultures. Overall this a transformative project that addresses significant gaps in our scientific knowledge. The proposal is innovative in conceptualizing PS1 as a key regulator of lysosome function and thus a significant contributor to proteostasis in general and tau more specifically. Further, technically it is innovative as we will be using an optogenetically driven proton pump to decrease the pH of lysosomes after PS1 knockdown to determine if maintaining an acidified lysosome is sufficient to restore its function. The IMPACT of these studies will be a significant contribution to our understanding of the role of PS1 in regulating tau biology via lysosomal function, thus informing general perspectives of neurobiological degeneration in aging. .

阿尔茨海默病（AD）以及其他老年发病的神经退行性疾病的共同特征是，是错误折叠、异常修饰的蛋白质的积累。在AD中，tau的聚集体是一种典型的标志形成这些蛋白质积聚的一个重要因素是功能障碍溶酶体依赖的降解途径。有趣的是，大多数常染色体显性遗传的家族性 AD（FAD）病例是由早老素1（PS1）突变引起的，PS1是阿尔茨海默氏症分泌酶的催化亚基。复合物，其也可能促进溶酶体功能。然而，PS 1在介导溶酶体中的作用生物学和tau的清除尚未完全阐明。根据之前的研究和我们的初步研究数据，这个提议的基本前提是，在神经元中，PS1在以下方面起着重要作用：调节溶酶体的功能，从而调节tau蛋白的周转。溶酶体在维持蛋白质停滞，因为多个降解途径将其货物引导至溶酶体进行降解/回收。溶酶体的活性或细胞内定位的改变有助于这些神经退行性疾病。鉴于溶酶体功能对神经元健康的重要性，了解PS1如何影响溶酶体生物学是非常重要的。关键的知识差距包括：PS1在原代神经元中的耗竭如何影响溶酶体pH，PS1耗竭对自噬体-溶酶体和内体-溶酶体融合，PS1耗竭对tau蛋白周转的影响， PS1耗竭的神经元中溶酶体的再酸化如何影响PS1诱导的溶酶体融合 Tau周转中的缺陷和不足。考虑到这些关键的知识差距，假设PS1的缺失导致溶酶体功能、定位和融合的损害事件，其对tau清除产生负面影响。在这一总体假设的背景下，这一特定目标我们的建议是验证以下假设：（1）PS1在酸化，活性和定位中发挥作用，溶酶体和其他降解囊泡在不同的神经元区室和（2）囊泡- 介导的加工/清除和tau的神经元内定位通过PS1的敲低而受损。这些将使用原代大鼠皮层神经元培养物进行研究。总的来说，这是一个变革性的项目，解决了我们科学知识中的重大空白。该提案在将PS1概念化为溶酶体功能的关键调节因子，因此是一般蛋白质稳定的重要贡献者，具体来说此外，在技术上，它是创新的，因为我们将使用光遗传学驱动的质子泵，在PS1敲低后降低溶酶体的pH，以确定维持酸化的溶酶体是否足以恢复其功能。这些研究的影响将是我们的重大贡献，了解PS1在通过溶酶体功能调节tau生物学中的作用，从而告知一般衰老中神经生物学退化的观点。 .