Function of TMEM106B in neurodegeneration

溶酶体跨膜蛋白TMEM 106 B最初被确定为具有颗粒蛋白（GRN）突变的额颞叶痴呆（FTD）的风险因素，最近与许多其他神经退行性疾病相关，包括阿尔茨海默病（AD），帕金森病和边缘主导的年龄相关TDP-43脑病（LATE）。TMEM 106 B也被认为是大脑衰老的主要决定因素之一。更有趣的是，最近发现TMEM 106 B内腔结构域中的D252 N突变可引起低髓鞘化脑白质营养不良（HLD）。然而，TMEM 106 B的细胞和生理功能仍有待确定。在我们的初步研究中，我们发现TMEM 106 B缺陷导致溶酶体聚集在核周区和溶酶体运输在轴突起始段（AIS）的阻滞。TMEM 106 B缺陷小鼠显示自噬缺陷和FTD相关病理学，如衰老期间磷酸化TDP-43蓄积。我们假设TMEM 106 B通过调节溶酶体运输和运动来调节髓鞘形成、自噬、脑老化和TDP-43病理。我们计划使用细胞生物学和生物化学方法来确定TMEM 106 B调节溶酶体定位、溶酶体沿沿着轴突运输和自噬流动的机制（Aim 1）。我们的研究还表明，TMEM 106 B在少突胶质细胞中高度表达，TMEM 106 B缺陷导致小鼠髓鞘形成缺陷。TMEM 106 B的消融导致髓磷脂膜蛋白PLP的运输缺陷，这是由于核周区域中的溶酶体聚集增加和溶酶体胞吐减少。我们计划进一步表征TMEM 106 B缺陷小鼠的髓鞘形成缺陷，特别是在AIS区域附近，并确定D252 N突变对TMEM 106 B功能和髓鞘形成（Aim 2）的影响。最后，我们发现TMEM 106 B和GRN两者缺陷的小鼠具有严重的溶酶体异常、神经胶质活化、神经变性和TDP-43聚集体的积累。我们计划使用小鼠模型和人类患者样本进一步剖析TMEM 106 B如何与GRN遗传相互作用以调节TDP-43病理学和FTD疾病进展（Aim 3）。总之，这些研究将揭示TMEM 106 B的细胞和生理功能，GRN和TMEM 106 B之间的遗传相互作用以及与TMEM 106 B相关的许多脑疾病的分子和细胞机制，包括HLD，LATE，AD和FTD。我们的工作还将产生新的见解，涉及调节AD，FTD和LATE中TDP-43聚集的机制，以及髓鞘形成缺陷如何导致AD，FTD和其他脑部疾病的神经退行性表型。

The lysosome transmembrane protein TMEM106B was originally identified as a risk factor for frontotemporal dementia (FTD) with granulin (GRN) mutations and was recently associated with many other neurodegenerative diseases, including Alzheimer’s (AD), Parkinson’s and limbic-predominant age-related TDP-43 encephalopathy (LATE). TMEM106B is also identified as one of the main determinants of brain aging. More interestingly, a D252N mutation in the lumenal domain of TMEM106B was recently found to cause hypomyelinating leukodystrophy (HLD). However, the cellular and physiological functions of TMEM106B remain to be determined. In our preliminary studies, we found that TMEM106B deficiency causes the clustering of lysosomes in the perinuclear region and a block of lysosome transport in the axon initial segment (AIS). TMEM106B deficient mice show autophagy defects and FTD related pathology such as accumulation of phosphorylated TDP-43 during aging. We hypothesize that TMEM106B regulates myelination, autophagy, brain aging and TDP-43 pathology via modulating lysosome trafficking and movement. We plan to determine the mechanisms by which TMEM106B regulates lysosome positioning, lysosome transport along axons and autophagy flow using cell biological and biochemical approaches (Aim1). Our studies have also shown that TMEM106B is highly expressed in oligodendrocytes and TMEM106B deficiency leads to myelination defects in mice. Ablation of TMEM106B leads to trafficking defects of the myelin membrane protein PLP due to increased lysosome clustering in the peri-nuclear region and decreased lysosome exocytosis. We plan to further characterize myelination defects of TMEM106B deficient mice, especially near the AIS region, and determine the effect of the D252N mutation on TMEM106B function and myelination (Aim2). Finally, we found that mice deficient in both TMEM106B and GRN have severe lysosome abnormalities, glial activation, neurodegeneration and accumulation of TDP-43 aggregates. We plan to further dissect how TMEM106B genetically interacts with GRN to regulate TDP-43 pathology and FTD disease progression using mouse models and human patient samples (Aim3). In summary, the proposed studies will shed light on cellular and physiological functions of TMEM106B, the genetic interaction between GRN and TMEM106B and the molecular and cellular mechanisms of many brain disorders with TMEM106B association, including HLD, LATE, AD and, FTD. Our work will also yield novel insights into mechanisms involved in regulating TDP-43 aggregation in AD, FTD and LATE and how myelination defects contribute to neurodegenerative phenotypes in AD, FTD and other brain disorders.