Abstract

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.

中文翻译：

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TMEM106B 编码变体在 tau 蛋白病小鼠模型中具有保护作用，而缺失则有害

摘要

TMEM106B 是多种神经系统疾病的风险调节剂，其中单个编码变体和多个非编码 SNP 影响易感性和恢复力之间的平衡。过去的工作中出现的两个关键问题是，单独的 T185S 编码变体是否有助于保护，以及 TMEM106B 的存在在疾病背景下是有益还是有害。在这里，我们解决了这两个问题，同时将 TMEM106B 研究范围从 TDP-43 扩展到 tau 蛋白病模型。我们生成了 TMEM106B 组成型缺失的敲除小鼠，以及编码 T186S 敲入突变（相当于人类 T185S 变体）的敲入小鼠，并将两者与 P301S 转基因 tau 模型杂交，以研究这些操作如何影响疾病表型。我们发现 TMEM106B 缺失会加速认知能力下降、后肢麻痹、tau 蛋白病理和神经退行性变。 TMEM106B 缺失还增加了与人类 AD 的转录相关性，并且 KO:tau 小鼠中丰富的功能通路与 AD 的功能通路一致。相比之下，编码变体可以防止 tau 相关的认知衰退、突触损伤、神经变性和瘫痪，而不影响 tau 病理学。我们的研究结果表明，TMEM106B 是防止 tau 蛋白聚集的重要保障，这种蛋白的缺失对 tau 蛋白病的后遗症具有深远的影响。我们的研究进一步表明，编码变体具有功能相关性，有助于 tau 病理学下游的神经保护，以保持认知功能。