Feng Tuancheng, Du Huan, Hu Fenghua
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
bioRxiv. 2023 Nov 15:2023.11.11.566707. doi: 10.1101/2023.11.11.566707.
, 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, 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, PS19 mice develop significantly increased disruption of the neuronal cytoskeleton, autophagy-lysosomal function, and lysosomal trafficking along the axon as well as enhanced gliosis compared with PS19 and 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.
一种编码溶酶体膜蛋白的基因TMEM106B与脑衰老、低髓鞘性脑白质营养不良以及多种神经退行性疾病紧密相关，包括伴有TDP - 43聚集体的额颞叶变性（FTLD - TDP）。最近，TMEM106B基因多态性与慢性创伤性脑病（CTE）和FTLD - TDP患者的tau蛋白病有关。然而，TMEM106B如何影响Tau病理及其相关的神经退行性变尚不清楚。在此我们表明，TMEM106B的缺失会增强病理性Tau的积累，尤其是在海马体的神经元胞体中，导致PS19 Tau转基因小鼠出现严重的神经元丢失。此外，与PS19和野生型小鼠相比，PS19小鼠神经元细胞骨架的破坏、自噬 - 溶酶体功能、沿轴突的溶酶体运输以及胶质增生均显著增加。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。
