U1 small nuclear RNA overexpression implicates autophagic-lysosomal system associated with AD
U1 small nuclear RNA overexpression implicates autophagic-lysosomal system associated with AD
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U1 小核 RNA 过度表达暗示自噬溶酶体系统与 AD 相关
DOI：
10.1016/j.neures.2018.01.006
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发表时间：
2018-11-01
影响因子：
2.9
通讯作者：
Zhang, Tao
中科院分区：
文献类型：
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作者：
Cheng, Zhi;Du, Zhanqiang;Zhang, Tao
最近，我们报道了早老素1显著增加U1小核RNA （snRNA）的表达水平，并伴随淀粉样蛋白前体蛋白（APP）表达、β -淀粉样蛋白（A β）产生和细胞凋亡的不利变化。本研究发现，U1 snRNA过表达可显著提高自噬的表达水平。此外，雷帕霉素进一步促进了A β的产生和细胞凋亡，而3-MA有效地抑制了这些过程。吖啶橙染色图像显示，U1 snRNA过表达不仅激活了细胞自噬途径，而且导致细胞自噬-溶酶体系统功能障碍。免疫荧光分析显示，AD毒蛋白主要成分的前体蛋白APP定位于自噬空泡。同时，U1 snRNA过表达可显著降低细胞超氧化物歧化酶活性，显著升高MDA水平，提示U1 snRNA过表达诱导细胞损伤存在可能的途径。我们进一步发现，U1 snRNA过表达改变了溶酶体的生物发生和自噬-溶酶体融合。结合我们之前的研究结果，这表明自噬途径的功能障碍为了解A β聚集增强和诱导细胞凋亡导致AD的分子机制提供了重要的见解。(c) 2018 Elsevier B.V.和日本神经科学学会。版权所有。
Recently, we reported that presenilin 1 considerably increased the expression level of U1 small nuclear RNA (snRNA) accompanied with the adverse change of amyloid precursor protein (APP) expression, beta-amyloid (A beta) production and cell apoptosis. In the present study, it was found that U1 snRNA overexpression significantly elevated the expression level of autophagy. Moreover, rapamycin further enhancedthe A beta production and cell apoptosis, whereas these processes were effectively inhibited by 3-MA. Acridine orange staining images showed that U1 snRNA overexpression not only activated autophagypathway, but also led to the autophagic- lysosomal system dysfunction in cells. Immunofluorescenceassay showed autophagic vacuoles localization with APP, which was the precursor protein of main component of toxic protein in AD. Meanwhile, the superoxide dismutase activity was remarkably decreasedand MDA level was significantly increased by U1 snRNA overexpression in cells, suggesting that therewas a possible pathway to elucidate how the U1 snRNA overexpression induced cell damage. We furtherfound that U1 snRNA overexpression altered lysosomal biogenesis and autophagic- lysosomal fusion. Incombination with our previous results, it suggests that the malfunction of autophagy pathway providesimportant insight into molecular mechanisms of augment the aggregation of A beta and induction of cell apoptosis contributed to AD. (c) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.