The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function
The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function
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DOI：
10.1093/hmg/dds475
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发表时间：
2013-02-15
影响因子：
3.5
通讯作者：
Hu, Fenghua
中科院分区：
文献类型：
--
作者：
Brady, Owen A.;Zheng, Yanqiu;Hu, Fenghua
颗粒蛋白前体（PGRN）是一种分泌型糖蛋白基因，其单倍不足是额颞叶退行性变伴泛素（FTLD-U）阳性包涵体的主要原因。最近发现TMEM 106 B基因的单核苷酸多态性是FTLD-U的危险因素，尤其是在PGRN突变患者中。TMEM 106 B还与肌萎缩侧索硬化症患者的认知障碍相关。尽管有这些研究，但在分子和细胞水平上对TMEM 106 B以及TMEM 106 B如何促成FTLD知之甚少。在这里，我们表明，TMEM 106 B定位于晚期内体/溶酶体隔室和TMEM 106 B水平受溶酶体活性调节。TMEM 106 B的异位表达诱导溶酶体区室的形态变化，并延迟内吞货物通过内溶酶体途径的降解。此外，TMEM 106 B的过表达与PGRN水平升高相关，可能通过减弱PGRN的溶酶体降解。这些结果阐明了TMEM 106 B的细胞功能以及TMEM 106 B在具有PGRN突变的FTLD-U的发病机制中的作用。
Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD. Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway. Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN. These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations.