Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway.
Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway.
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DOI：
10.1111/jnc.13011
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发表时间：
2015-05
影响因子：
4.7
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Chu J;Li JG;Hoffman NE;Madesh M;Praticò D
阿尔茨海默病（AD）的一个主要标志性特征是淀粉样蛋白β（Aβ）的积累，其形成受γ-分泌酶复合物及其活化蛋白（也称为γ-分泌酶活化蛋白，或GSAP）调节。由于GSAP与γ-分泌酶相互作用而不影响Notch的切割，因此它是可行的抗A β治疗的理想靶标。GSAP通过半胱天冬酶-3介导的切割衍生自98 kDa的较大前体蛋白的C-末端片段。然而，其降解机制尚不清楚。在目前的论文中，我们表明GSAP具有约5小时的短半衰期。用蛋白酶体抑制剂处理的神经元细胞显著阻止GSAP蛋白降解，这与Aβ水平和γ-分泌酶裂解产物的显著增加有关。相比之下，钙蛋白酶阻断剂和溶酶体抑制剂的治疗没有效果。此外，我们提供了实验证据表明GSAP是泛素化的。总之，我们的研究结果表明，GSAP是通过泛素-蛋白酶体系统降解。GSAP降解途径的调节可以作为AD中更安全的抗A β治疗方法的可行靶点。
A major hallmark feature of Alzheimer’s disease (AD) is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as γ-secretase activating protein, or GSAP). Because GSAP interacts with the γ-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. GSAP derives from a C-terminal fragment of a larger precursor protein of 98kDa via a caspase-3-mediated cleavage. However, the mechanism(s) involved in its degradation are unknown. In the current paper, we show that GSAP has a short half-life of approximately 5 hours. Neuronal cells treated with proteasome inhibitors markedly prevented GSAP protein degradation, which was associated with a significant increment in Aβ levels and γ-secretase cleavage products. By contrast, treatment with calpain blocker and lysosome inhibitors had no effect. In addition, we provide experimental evidence that GSAP is ubiquitinated. Taken together, our findings reveal that GSAP is degraded through the ubiquitin-proteasome system. Modulation of the GSAP degradation pathway may be implemented as a viable target for a safer anti-Aβ therapeutic approach in AD.
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