TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b^−/− PS19 mice develop significantly increased abnormalities in the neuronal cytoskeleton, autophagy-lysosome activities, as well as glial activation, compared with PS19 and Tmem106b^−/− mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.

TMEM106B是一种编码溶酶体膜蛋白的基因，与大脑衰老、髓鞘形成低下性脑白质营养不良和多种神经退行性疾病密切相关，包括 TDP-43 聚集导致的额颞叶变性 (FTLD-TDP)。最近，TMEM106B多态性与慢性创伤性脑病 (CTE) 和 FTLD-TDP 患者的 tau 蛋白病相关。然而，TMEM106B 如何影响 Tau 病理学及其相关的神经变性尚不清楚。在这里，我们发现TMEM106B的缺失会增强病理性Tau的积累，特别是在海马的神经元胞体中，导致PS19 Tau转基因小鼠严重的神经元损失。此外，与 PS19 和Tmem106b ^−/−小鼠相比， Tmem106b ^−/− PS19 小鼠的神经元细胞骨架、自噬溶酶体活性以及神经胶质活化异常显着增加。总之，我们的研究结果表明，TMEM106B 的缺失会极大加剧 Tau 病理学及其相关疾病表型，并为 TMEM106B 在神经退行性疾病中的作用提供新的见解。