TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia
TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia
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DOI：
10.1111/jnc.12329
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发表时间：
2013-09-01
影响因子：
4.7
通讯作者：
Rademakers, Rosa
中科院分区：
文献类型：
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作者：
Nicholson, Alexandra M.;Finch, NiCole A.;Rademakers, Rosa
额颞叶变性（FTLD）是65岁以下人群痴呆症的第二大原因。在许多患者中，主要病理包括泛素化TAR DNA结合蛋白43 （FTLD-TDP）的神经元胞质或核内包涵体。最近，一项全基因组关联研究发现了第一个FTLD-TDP遗传风险因素，其中TMEM106B基因及其周围的变异（顶部SNP rs1990622）与FTLD-TDP风险显著相关。有趣的是，最显著的关联是在携带颗粒前蛋白（GRN）突变的FTLD-TDP患者。在这里，我们研究了编码变异rs3173615 （p. T185S）与rs1990622连锁不平衡在多大程度上影响颗粒蛋白前蛋白（PGRN）生物学和跨膜蛋白106B （TMEM106B）调控。首先，我们在新的GRN突变携带者队列中证实了tmem106b变体与FTLD-TDP的关联。接下来，我们生成并鉴定了一种tmem106b特异性抗体，用于研究该蛋白。酶联免疫分析显示，蛋白前蛋白水平对T185和S185 TMEM106B过表达有相似的影响。然而，T185的过表达始终导致TMEM106B蛋白水平高于S185。环己亚胺处理实验表明，S185降解速度快于T185 TMEM106B，可能是由于残基N183上n -糖基化的差异。总之，我们的研究结果提供了TMEM106B变异导致FTLD-TDP风险差异的潜在机制。
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p. T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106Bvariants with FTLD-TDP in anew cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression. However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.