TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
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DOI：
10.1126/scitranslmed.3009093
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发表时间：
2014-07-02
影响因子：
17.1
通讯作者：
Haass, Christian
中科院分区：
文献类型：
--
作者：
Kleinberger, Gernot;Yamanishi, Yoshinori;Haass, Christian
髓样细胞上表达的触发受体2（TREM 2）中的遗传变异与Nasu-Hakola病、阿尔茨海默病（AD）、帕金森病、肌萎缩侧索硬化症、额颞叶痴呆（FTD）和无骨受累的FTD样综合征相关。TREM 2是由小胶质细胞优先表达的先天性免疫受体，并参与炎症和吞噬作用。TREM 2错义突变是否以及如何影响TREM 2功能尚不清楚。我们报告了与FTD和FTD样综合征相关的错义突变减少了TREM 2成熟，消除了ADAM蛋白酶的脱落，并损害了TREM 2表达细胞的吞噬活性。作为减少脱落的结果，TREM 2实际上不存在于患有FTD样综合征的患者的脑脊液（CSF）和血浆中。在AD和FTD患者的CSF中也观察到可溶性TREM 2降低，进一步表明TREM 2功能降低可能导致两种神经退行性疾病的风险增加。
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.