Mutations in GRN, which encodes progranulin, are a common cause of familial frontotemporal dementia (FTD). FTD is a devastating disease characterised by neuronal loss in the frontal and temporal lobes that leads to changes in personality, behaviour and language. There are no effective treatments for this complex condition. TMEM106B is a well‐recognised risk factor for FTD caused by GRN mutation. While the specific relationship between progranulin and TMEM106B is unclear, it is well established that they are both required for correct lysosome function and trafficking. Elegant experiments have suggested that increased risk for FTD is due to elevated levels of TMEM106B (Nicholson et al, 2013; Gallagher et al, 2017). Therefore, recent work has explored the therapeutic potential of reducing TMEM106B levels, with initial results looking encouraging, as crossing a Grn‐deficient mouse to a Tmem106b knockout showed a rescue in FTD‐related behavioural defects and specific aspects of lysosome dysfunction (Klein et al, 2017). However, three independent studies in this issue report that completely removing Tmem106b from Grn knockout mice leads to clear exacerbation of phenotypes, causing severe motor deficits, neurodegeneration and enhanced lysosome abnormalities and gliosis. Remarkably, the double knockout mice also develop TDP‐43 pathology—a hallmark of FTD patients with GRN mutations that have not been consistently observed in either of the single knockouts. These concurrent publications that all reach the same surprising but definitive conclusion are a cautionary tale in the control of TMEM106B levels as a potential therapeutic for FTD. They also re‐ignite the debate as to whether loss or gain of TMEM106B function is critical for altering FTD risk.

中文翻译：

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Progranulin 和 TMEM106B：当两个变淡时

编码颗粒蛋白前体的GRN突变是家族性额颞叶痴呆 (FTD) 的常见原因。FTD 是一种破坏性疾病，其特征是额叶和颞叶的神经元丧失，导致人格、行为和语言的变化。这种复杂的情况没有有效的治疗方法。TMEM106B是公认的由GRN突变引起的 FTD 的危险因素。虽然颗粒蛋白前体和 TMEM106B 之间的具体关系尚不清楚，但众所周知，它们都是正确的溶酶体功能和运输所必需的。优雅的实验表明，FTD 风险增加是由于 TMEM106B 水平升高（Nicholson等，2013；Gallagher等, 2017)。因此，最近的工作探索了降低 TMEM106B 水平的治疗潜力，初步结果看起来令人鼓舞，因为将Grn缺陷小鼠与Tmem106b敲除表明 FTD 相关的行为缺陷和溶酶体功能障碍的特定方面得到拯救（Klein等人, 2017)。然而，本期中的三项独立研究报告称，从Grn敲除小鼠中完全去除Tmem106b会导致表型明显恶化，导致严重的运动缺陷、神经退行性变和溶酶体异常和神经胶质增生增强。值得注意的是，双基因敲除小鼠也会出现 TDP-43 病理学——这是患有GRN的 FTD 患者的标志在任何一次敲除中都没有始终如一地观察到突变。这些同时发表的出版物都得出了相同的令人惊讶但明确的结论，是控制 TMEM106B 水平作为 FTD 潜在治疗剂的警示故事。他们还重新引发了关于 TMEM106B 功能的丧失或获得对于改变 FTD 风险是否至关重要的争论。