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

摘要 TMEM 106 B作为疾病风险的修饰剂首次引起神经变性社区的注意， FTLD-TDP，其中保护性单倍型在受试者中显著低于健康对照。 自从这一发现以来，TMEM 106 B的保护作用已经扩展到衰老中的海马硬化， ALS和PD中的认知症状，大脑老化的转录指标，以及抗 神经病理学负担考虑到它的影响，我们对TMEM 106 B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 内容，但其对溶酶体功能的影响却不那么确定。保护性TMEM 106 B 单体型转录活性低于常见（风险）变体和唯一识别的编码SNP 似乎增加蛋白质周转，共同表明TMEM 106 B水平的轻度降低可能是 最佳认知健康。基于过去的研究，我们假设TMEM 106 B调节溶酶体， 通过溶酶体处的局部蛋白质相互作用和通过经由TFEB的核信号传导来维持体内平衡。 我们进一步提出，这种作用在衰老和疾病中变得更加关键，其中溶酶体功能必须 在细胞压力下维持。作为测试TMEM 106 B水平或亚型如何影响 溶酶体的组成和功能在健康的大脑和老化或神经病理学的压力下，我们有 产生了等位基因系列的小鼠，其中TMEM 106 B水平已被组成性降低、缺失或缺失， 被编码变体取代。在我们的第一个目标中，我们将测试TMEM 106 B水平如何影响溶酶体pH，大小， 和分解代谢功能在健康的大脑和老化和tau蛋白病的条件下。在我们的第二个目标，我们 将测试TMEM 106 B是否通过局部蛋白质相互作用、核相互作用和核相互作用影响溶酶体组成。 转录或两者。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TMEM 106 B定位 和溶酶体性质，以确定该变体是否部分表型模仿TMEM 106 B的功能丧失。 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， 溶酶体免疫沉淀的力量，以获得一个公正的和近距离的看法，溶酶体如何 TMEM 106 B对催化剂的组成和催化性能有影响。TMEM 106 B的作用尚待澄清， 现有的文献关于其对细胞的影响是矛盾的。但是通过在体内处理这种蛋白质， 使用我们计划提供的工具和技术，我们拥有无与伦比的 有机会最终确定这种蛋白质如何影响与以下相关的细胞中的溶酶体功能 阿尔茨海默病和在老化和tau蛋白病的条件下，参加痴呆症。最终，我们希望 我们的工作将为这个无法描述的溶酶体所具有的巨大影响力提供机械的见解， 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.