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

• 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
• 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' 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

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首先引起了神经退行性社区的注意，这是疾病风险的修饰。 FTLD-TDP，保护性单倍型在受试者中的普遍性明显少于健康对照组。 自从这一发现以来，TMEM106B的保护作用已扩展到衰老的海马硬化症， ALS和PD的认知症状，大脑衰老的转录指标以及功能弹性 神经病理学负担。鉴于它的影响，我们对TMEM106B功能的了解鲜为人知。 TMEM106B 位于晚期的内体和溶酶体，过去的工作表明它调节囊泡大小和酶 内容，但对其对溶酶体功能的影响的确定性要差得多。保护性TMEM106B 单倍型比共同（风险）变体和唯一确定的编码SNP的转录活性较低 似乎增加了蛋白质的转换，同时表明TMEM106B水平的轻度降低可能是 最佳认知健康。根据过去的研究，我们假设TMEM106B调节溶酶体 通过溶酶体处的局部蛋白质相互作用和通过TFEB核信号传导的稳态。 我们进一步建议，这种作用在衰老和疾病中变得更加关键，溶酶体功能必须 保持在细胞应激下。作为测试TMEM106B或同工型如何影响的平台 溶酶体组成和健康大脑中的功能以及在衰老或神经病理学的压力下，我们有 产生了一系列等位基因小鼠，其中TMEM106B水平已被组成率降低，删除或 用编码变体代替。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， 在健康的大脑以及衰老和tauopathy的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，核能影响溶酶体组成 转录，或两者兼而有之。在我们的最终目标中，我们将测试唯一的编码变体如何影响TMEM106B本地化 和溶酶体特性，以确定这种变体是否部分地表观tmem106b功能丧失。 在每个目标中，我们都将利用代谢组学和蛋白质组学的技术能力以及 溶酶体免疫沉淀的能力，以获得无偏见和近距离的视野 组成和分解代谢受TMEM106B的影响。 TMEM106B的作用尚未澄清，并且 现有文献对其对细胞的影响有冲突。但是通过在本机下在体内解决这种蛋白质 使用我们程序提供的工具和技术的表达条件，我们有一个无与伦比的 最终确定该蛋白如何影响与细胞中溶酶体功能的机会 阿尔茨海默氏病以及在衰老和痴呆症患者的疾病下。最终，我们希望 我们的工作将提供对这种非描述性溶酶体所具有的超大影响的机械洞察力 蛋白质跨越不断增长的神经退行性条件。