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

摘要 年，TMEM106B作为疾病风险的修饰物首次引起了神经退行性变社区的注意 FTLD-TDP，其中保护性单倍型在受试者中显著低于健康对照组。 自从这一发现以来，TMEM106B的保护作用已经扩展到老化的海马区硬化， 肌萎缩侧索硬化症和帕金森病的认知症状、脑老化的转录指标以及对 神经病理负担。考虑到它的影响，我们对TMEM106B的功能知之甚少。TMEM106B 定位于晚期的内小体和溶酶体，过去的研究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还不是很确定。保护性的TMEM106B 单倍型的转录活性低于常见的(风险)变异体，也是唯一已识别的编码SNP 似乎增加了蛋白质周转，共同表明TMEM106B水平的轻微降低可能是 对认知健康最有利。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的核信号实现动态平衡。 我们进一步提出，这种作用随着年龄的增长和疾病而变得更加关键，溶酶体的功能必须 在细胞压力下维持。作为测试TMEM106B水平或异构体影响的平台 在健康的大脑和在衰老或神经病理的压力下，我们有溶酶体的组成和功能 产生了一系列等位基因小鼠，其中TMEM106B水平已经结构性地降低、缺失或 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的pH，大小， 和分解代谢功能在健康的大脑和在衰老和肌萎缩侧索硬化症条件下。在我们的第二个目标，我们 将测试TMEM106B是否通过局部蛋白质相互作用、核 转录，或者两者兼而有之。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 和溶酶体的特性来确定该变异是否部分复制了TMEM106B的功能。 在每个目标中，我们将利用我们的代谢组学和蛋白质组学核心的技术能力以及 溶酶体免疫沉淀获得不偏不倚和近距离观察溶酶体如何 TMEM106B对其组成和分解代谢有影响。TMEM106B的作用尚未明确， 现有的文献对其对细胞的影响相互矛盾。但通过在体内天然条件下处理这种蛋白质 表达条件使用我们计划提供的工具和技术，我们拥有无与伦比的 最终确定该蛋白如何影响与以下相关的细胞中的溶酶体功能的机会 阿尔茨海默氏症，在衰老和肌萎缩侧索硬化症的条件下出现痴呆症。最终，我们希望 我们的工作将提供对这种非描述溶酶体所具有的超大影响的机械洞察力 在越来越多的神经退行性疾病中的蛋白质。

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.