Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease
Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease
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DOI：
10.1016/j.bbadis.2012.07.015
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发表时间：
2012-11-01
影响因子：
6.2
通讯作者：
Eleuteri, Anna Maria
中科院分区：
文献类型：
--
作者：
Cecarini, Valentina;Bonfili, Laura;Eleuteri, Anna Maria
阿尔茨海默病是最常见的进行性神经退行性疾病，其特征在于淀粉样蛋白斑块的异常沉积，可能是淀粉样蛋白-β前体蛋白（A β PP）的不正确加工的结果。还观察到泛素-蛋白酶体系统和自噬的功能障碍。最近，这两种降解途径之间出现了广泛的串扰，但确切的牵连过程尚未澄清。在这项工作中，我们通过分析稳定转染野生型A β PP基因或717缬氨酸-甘氨酸A β PP突变基因的人SH-SY 5 Y神经母细胞瘤细胞，深入了解了这种相互作用。A β PP突变体亚型的过度表达与氧化应激的增加和蛋白质降解的重塑模式相关，同时显著抑制蛋白酶体活性和损伤自噬通量。为了补偿这种改变的情况，细胞试图以HDAC 6依赖性方式促进自噬激活。用淀粉样蛋白-β（42）寡聚体处理进一步损害蛋白酶体活性，并且还有助于抑制组织蛋白酶介导的蛋白水解，最终有利于神经元变性，并且表明存在A β（42）阈值水平，超过该阈值水平，蛋白酶体依赖性蛋白水解变得明确地功能障碍。(C)2012爱思唯尔有限公司版权所有。
Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-beta precursor protein (A beta PP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type A beta PP gene or 717 valine-to-glycine A beta PP-mutated gene. The over-expression of the A beta PP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-beta(42) oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an A beta(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional. (C) 2012 Elsevier B.V. All rights reserved.