TMEM106B encodes a lysosomal membrane protein and was initially identified as a risk factor for frontotemporal lobar degeneration. Recently, a dominant D252N mutation in TMEM106B was shown to cause hypomyelinating leukodystrophy. However, how TMEM106B regulates myelination is still unclear. Here we show that TMEM106B is expressed and localized to the lysosome compartment in oligodendrocytes. TMEM106B deficiency in mice results in myelination defects with a significant reduction of protein levels of proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), the membrane proteins found in the myelin sheath. The levels of many lysosome proteins are significantly decreased in the TMEM106B-deficient Oli-neu oligodendroglial precursor cell line. TMEM106B physically interacts with the lysosomal protease cathepsin D and is required to maintain proper cathepsin D levels in oligodendrocytes. Furthermore, we found that TMEM106B deficiency results in lysosome clustering in the perinuclear region and a decrease in lysosome exocytosis and cell surface PLP levels. Moreover, we found that the D252N mutation abolished lysosome enlargement and lysosome acidification induced by wild-type TMEM106B overexpression. Instead, it stimulates lysosome clustering near the nucleus as seen in TMEM106B-deficient cells. Our results support that TMEM106B regulates myelination through modulation of lysosome function in oligodendrocytes.

中文翻译：

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额颞叶变性危险因子TMEM106B在髓鞘形成中的作用。

TMEM106B编码溶酶体膜蛋白，最初被确定为额颞叶变性的危险因素。最近，显示出TMEM106B中的显性D252N突变会引起髓鞘性白细胞营养不良。但是，尚不清楚TMEM106B如何调节髓鞘形成。在这里，我们显示TMEM106B在少突胶质细胞中表达并定位于溶酶体区室。小鼠中的TMEM106B缺乏会导致髓鞘形成缺陷，并显着降低蛋白脂质蛋白（PLP）和髓磷脂少突胶质细胞糖蛋白（MOG）（在髓鞘中发现的膜蛋白）的蛋白水平。在TMEM106B缺陷的Oli-neu少突胶质前体细胞系中，许多溶酶体蛋白的水平显着降低。TMEM106B与溶酶体蛋白酶组织蛋白酶D发生物理相互作用，需要TMEM106B维持少突胶质细胞中适当的组织蛋白酶D水平。此外，我们发现TMEM106B缺乏会导致核周区域中的溶酶体簇集，并导致溶酶体胞吐作用和细胞表面PLP水平降低。此外，我们发现D252N突变消除了野生型TMEM106B过表达诱导的溶酶体扩增和溶酶体酸化。而是，它刺激了核附近的溶酶体簇，如在TMEM106B缺陷细胞中所见。我们的结果支持TMEM106B通过调节少突胶质细胞中的溶酶体功能来调节髓鞘形成。我们发现，TMEM106B缺乏会导致核周区域内溶酶体聚集，并导致溶酶体胞吐作用和细胞表面PLP水平降低。此外，我们发现D252N突变消除了野生型TMEM106B过表达诱导的溶酶体扩增和溶酶体酸化。而是，它刺激了核附近的溶酶体簇，如在TMEM106B缺陷细胞中所见。我们的结果支持TMEM106B通过调节少突胶质细胞中的溶酶体功能来调节髓鞘形成。我们发现，TMEM106B缺乏会导致核周区域内溶酶体聚集，并导致溶酶体胞吐作用和细胞表面PLP水平降低。此外，我们发现D252N突变消除了野生型TMEM106B过表达诱导的溶酶体扩增和溶酶体酸化。而是，它刺激了核附近的溶酶体簇，如在TMEM106B缺陷细胞中所见。我们的结果支持TMEM106B通过调节少突胶质细胞中的溶酶体功能来调节髓鞘形成。