The effect and mechanism of 19S proteasome PSMD11/Rpn6 subunit in D-Galactose induced mimetic aging models
The effect and mechanism of 19S proteasome PSMD11/Rpn6 subunit in D-Galactose induced mimetic aging models
复制标题
19S蛋白酶体PSMD11/Rpn6亚基在D-半乳糖诱导的模拟衰老模型中的作用及机制
DOI：
10.1016/j.yexcr.2020.112093
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发表时间：
2020
影响因子：
3.7
通讯作者：
Weijia Kong
中科院分区：
文献类型：
--
作者：
Han Wu;Haiying Sun;Zuhong He;Xi Chen;Yongqin Li;Xueyan Zhao;Wen Kong;Weijia Kong
调节蛋白酶体活性是老年性听力损失的有效治疗方面，已被证明可以保护神经元免受老年性损伤。PSMD11是19S蛋白酶体调节颗粒的亚基，主要起到上调蛋白酶体活性和延缓衰老的作用。然而，PSMD11在年龄相关性听力损失中的作用机制尚未深入探讨。在本研究中，我们探讨了PSMD11在半乳糖（D-Gal）模拟衰老模型中保护神经元的功能和机制。采用Taq-PCR、ABR、透射电镜、甲苯胺蓝、β-半乳糖苷酶染色检测年龄相关病变。Western blotting、oxyblot、免疫沉淀、免疫荧光检测各蛋白的相对表达情况。流式细胞术检测氧化状态。我们发现蛋白酶体活性随着衰老而受损，并且在D-Gal诱导的衰老模型中ROS和有毒蛋白积累。PSMD11随着衰老而变化，并与D-Gal处理模型中蛋白酶体活性的代谢有关。PSMD11的敲低或过表达足以改变D-Gal引起的氧化状态。我们的研究结果还表明，PSMD11可以与听觉皮层和PC12细胞中的AMPKα1/2结合，AMPKα2而不是AMPKα1有效调节PSMD11的功能。我们需要更深入地了解PSMD11在抗衰老过程中的调节机制，并可能为中枢性老年性痴呆提供新的治疗方法。
Regulating proteasome activity is a potent therapeutic aspect of age-related hearing loss, which has been proven to protect neurons from age-related damaging. PSMD11, subunit of the 19S proteasome regulatory particle, is known to mainly up-regulate proteasome activity and prolong aging. However, the mechanism of PSMD11 in age-related hearing loss has not been deeply explored. In the present study, we explore the function and mechanism of PSMD11 protecting neurons ind-Galactose (D-Gal) mimetic aging models. Age-related pathologies were detected by Taq-PCR, ABR, Transmission electron microscopy, toluidine blue and β-galactosidase staining. The relative expressions of the proteins were explored by Western blotting, oxyblot, immunoprecipitation and immunofluorescence. Flow cytometry was used to manifest the oxidative state. We discovered that proteasome activity was impaired with aging, and that ROS and toxic protein accumulated in D-Gal induced aging models. PSMD11 changed with aging, and was associated with the metabolism of proteasome activity in the D-Gal treated models. Moreover, the knockdown or overexpression of PSMD11 was sufficient to change the oxidative state caused by D-Gal. Our results also demonstrated that PSMD11 could bond to AMPKα1/2 in the auditory cortex and PC12 cells, and AMPKα2 but not AMPKα1 was efficient to regulate the function of PSMD11. Deeper insights into the mechanisms of regulating PSMD11 for the anti-aging process are needed, and may offer novel therapeutic methods for central presbycusis.