TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis

TMEM106b 作为溶酶体适配器影响大脑衰老和 tau 发病机制

基本信息

批准号：
10583546
负责人：
JOANNA L JANKOWSKY
金额：
$ 52.62万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583546
关键词：
Adult Affect Age Aging Alleles Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Attention Biology Brain Catabolism Cells Cellular Stress Characteristics Code Cognitive Communities Consensus Sequence Data Set Dementia Disease Enzymes Frontotemporal Dementia Frontotemporal Lobar Degenerations Gene Expression Profile Genetic Complementation Test Genetic Transcription Half-Life Haplotypes Health Homeostasis Human Immunoprecipitation Impaired cognition In Vitro Integral Membrane Protein Knock-in Mouse Knock-out Knockout Mice Lead Link Linkage Disequilibrium Literature Lysosomes Maps Measures Mediating Modification Molecular Mus Nerve Degeneration Neurobehavioral Manifestations Neurons Nuclear Parkinson Disease Pathogenesis Pathology Phenocopy Post-Translational Protein Processing Property Protein Isoforms Proteins Proteomics Regulation Risk Role Series Signal Transduction Site Stress Tauopathies Technology Testing Transfection Uncertainty Variant Vesicle Work aging brain brain cell brain tissue cell motility cell type disorder risk genetic risk factor glycosylation hippocampal sclerosis human subject in vivo insight knock-down late endosome lens loss of function lysosomal proteins metabolomics nervous system disorder neuropathology overexpression preservation programs protein degradation resilience single nucleus RNA-sequencing synergism tau Proteins tool transcriptome sequencing vacuolar H+-ATPase

项目摘要

Abstract TMEM106B first came to the attention of the neurodegeneration community as a modifier of disease risk in FTLD-TDP, where the protective haplotype was significantly less common in subjects than in healthy controls. Since this discovery, TMEM106B's protective influence has been extended to hippocampal sclerosis in aging, cognitive symptoms in ALS and PD, transcriptional indicators of brain aging, and functional resilience against neuropathological burden. Given its impact, we know surprisingly little about TMEM106B function. TMEM106B is localized to the late endosome and lysosome where past work suggests it regulates vesicle size and enzyme content, but has been much less definitive about its effect on lysosomal function. The protective TMEM106B haplotype is less transcriptionally active than the common (risk) variant and the only coding SNP identified appears to increase protein turnover, together suggesting that mild reduction of TMEM106B levels may be optimal for cognitive health. Based on past studies, we hypothesize that TMEM106B regulates lysosomal homeostasis through both local protein interactions at the lysosome and through nuclear signaling via TFEB. We further propose that this role becomes more critical with aging and disease, where lysosomal function must be maintained under cellular stress. As a platform for testing how TMEM106B levels or isoform impact lysosome composition and function in the healthy brain and under stress of aging or neuropathology, we have generated an allelic series of mice in which TMEM106B levels have been constitutively reduced, deleted, or substituted with a coding variant. In our first aim, we will test how TMEM106B levels affect lysosome pH, size, and catabolic function in the healthy brain and under conditions of aging and tauopathy. In our second aim, we will test whether TMEM106B influences lysosomal composition through local protein interactions, nuclear transcription, or both. In our final aim, we will test how the lone coding variant affects TMEM106B localization and lysosomal properties to determine whether this variant partially phenocopies TMEM106B loss of function. In each aim, we will leverage the technical capabilities of our Metabolomics and Proteomics Cores and the power of lysosomal immunoprecipitation to obtain an unbiased and up-close view of how lysosome composition and catabolism is influenced by TMEM106B. The role of TMEM106B has yet to be clarified and the existing literature is conflicted about its impact on the cell. But by tackling this protein in vivo under native expression conditions using the tools and technologies afforded by our Program, we have an unparalleled opportunity to conclusively determine how this protein influences lysosomal function in cells relevant to Alzheimer's disease and under conditions of aging and tauopathy that attend dementia. Ultimately, we hope that our work will offer mechanistic insight into the outsized influence held by this non-descript lysosomal protein across a growing swath of neurodegenerative conditions.

抽象的 TMEM106B 作为疾病风险的修饰剂首次引起神经退行性疾病界的关注 FTLD-TDP，其中保护性单倍型在受试者中明显低于健康对照。自这一发现以来，TMEM106B 的保护作用已扩展到衰老过程中的海马硬化， ALS 和 PD 的认知症状、大脑衰老的转录指标以及针对疾病的功能恢复能力神经病理负担。鉴于其影响，我们对 TMEM106B 的功能知之甚少。 TMEM106B 定位于晚期内体和溶酶体，过去的研究表明它调节囊泡大小和酶含量，但对其对溶酶体功能的影响还不太明确。保护性TMEM106B 单倍型的转录活性低于常见（风险）变体，并且是唯一已识别的编码 SNP 似乎增加了蛋白质周转率，同时表明 TMEM106B 水平的轻度降低可能是最适合认知健康。根据过去的研究，我们假设 TMEM106B 调节溶酶体通过溶酶体的局部蛋白质相互作用和通过 TFEB 的核信号传导实现稳态。我们进一步提出，随着衰老和疾病的发生，这一作用变得更加重要，其中溶酶体功能必须维持在细胞应激状态下。作为测试 TMEM106B 水平或亚型影响的平台健康大脑中的溶酶体组成和功能以及在衰老或神经病理学压力下，我们有产生了一系列等位基因小鼠，其中 TMEM106B 水平已被组成性降低、删除或替换为编码变体。在我们的第一个目标中，我们将测试 TMEM106B 水平如何影响溶酶体 pH、大小、健康大脑以及衰老和 tau 蛋白病条件下的分解代谢功能。在我们的第二个目标中，我们将测试 TMEM106B 是否通过局部蛋白质相互作用、核转录，或两者兼而有之。在我们的最终目标中，我们将测试单独的编码变体如何影响 TMEM106B 本地化和溶酶体特性，以确定该变体是否部分表型复制 TMEM106B 功能丧失。在每个目标中，我们将利用代谢组学和蛋白质组学核心的技术能力以及溶酶体免疫沉淀的力量可以获得关于溶酶体如何进行无偏见且近距离的观察组成和分解代谢受 TMEM106B 影响。 TMEM106B 的作用尚未明确，现有文献对其对细胞的影响存在争议。但是通过在天然条件下体内处理这种蛋白质使用我们的计划提供的工具和技术来表达条件，我们拥有无与伦比的有机会最终确定该蛋白质如何影响相关细胞中的溶酶体功能阿尔茨海默病以及衰老和 tau 蛋白病导致的痴呆症。最终，我们希望我们的工作将为这种非描述性溶酶体所具有的巨大影响提供机制上的洞察蛋白质在越来越多的神经退行性疾病中发挥作用。