State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-Cerebrovascular Diseases, and Institute of New Drug Research, Jinan University College of Pharmacy, 601# Huangpu Road, Guangzhou, 510632, China.
School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, China.
Neuromolecular Med. 2024 Apr 3;26(1):9. doi: 10.1007/s12017-024-08775-4.
Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin-proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αβ and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN's effects on Psmb8, Pa28αβ, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.
α-突触核蛋白（α-syn）的聚集和 α-syn 的细胞毒性是散发性和家族性帕金森病（PD）的标志。核因子（红系衍生 2）样 2（Nrf2）依赖性增强 20S 蛋白酶体核心颗粒（20S CPs）和调节颗粒（RPs）的表达可增加蛋白酶体活性，从而促进 PD 中 α-syn 的清除。过氧化物酶体增殖物激活受体 γ 共激活物 1α（PGC-1α）的激活可能通过强烈诱导 Nrf2 基因表达来减少氧化应激。在本研究中，四甲基吡嗪硝酮（TBN），一种有效的自由基清除剂，可促进过表达人 A53T 突变 α-syn 的细胞模型中泛素蛋白酶体系统（UPS）清除 α-syn。在 α-syn 转基因小鼠模型中，TBN 改善了运动障碍，降低了氧化损伤产物的水平，并下调了血清中的 α-syn 水平。TBN 一致地上调了 PD 测试模型中的 PGC-1α 和 Nrf2 的表达。此外，TBN 同样增强了蛋白酶体 20S 亚基β8（Psmb8）的表达，这与糜蛋白酶样蛋白酶体活性有关。此外，TBN 增加了 11S RPs 亚基 Pa28αβ 和一种蛋白酶体伴侣，即蛋白酶体成熟蛋白（Pomp）的 mRNA 水平。有趣的是，针对 Nrf2 的特异性 siRNA 阻断了 TBN 对 Psmb8、Pa28αβ、Pomp 表达和 α-syn 清除的作用。总之，TBN 通过 Nrf2 介导的 UPS 激活促进了 α-syn 的清除，它可能成为治疗 PD 的一种潜在的疾病修饰治疗剂。
