Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA.
Acta Neuropathol. 2024 Mar 25;147(1):62. doi: 10.1007/s00401-024-02702-4.
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，与脑老化、脱髓鞘性白质脑病以及多种神经退行性疾病密切相关，包括伴有 TDP-43 聚集的额颞叶变性（FTLD-TDP）。最近，TMEM106B 多态性与慢性创伤性脑损伤（CTE）和 FTLD-TDP 患者的 tau 病有关。然而，TMEM106B 如何影响 Tau 病理学及其相关的神经退行性变尚不清楚。在这里，我们发现 TMEM106B 的缺失会增强病理性 Tau 的积累，特别是在海马神经元体中，导致 PS19 Tau 转基因小鼠中严重的神经元丢失。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激活的异常显著增加。总之，我们的研究结果表明，TMEM106B 的缺失会极大地加剧 Tau 病理学及其相关的疾病表型，并为 TMEM106B 在神经退行性疾病中的作用提供了新的见解。
