Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China; Evaluation and Monitoring Center of Occupational Health, Guangzhou Twelfth People's Hospital, Guangzhou, PR China.
Free Radic Biol Med. 2022 Mar;181:82-97. doi: 10.1016/j.freeradbiomed.2022.02.001. Epub 2022 Feb 3.
Mitochondrial dysfunction, oxidative stress and misfolded protein aggregation are related to autophagy-lysosomal dysregulation and contribute to the pathogenesis of Parkinson' s disease (PD). ZKSCAN3, a transcriptional repressor, plays a crucial role in autophagy and lysosomal biogenesis. However, the role and modification of ZKSCAN3 in the defection of ALP, along with the molecular mechanism involved in pathogenesis of PD, still remain unclear. In this study, we demonstrated that cellular reactive oxygen species (ROS) generated by MPP exposure and the resulting oxidative damage were counteracted by SIRT1-ZKSCAN3 pathway induction. Here we showed that nuclear ZKSCAN3 significantly increased in ventral midbrain of MPTP-treated mice and MPP-treated SN4741 cells. Knockdown of ZKSCAN3 alleviated MPP-induced ALP defect, Tyrosine Hydroxylase (TH) declination and neuronal death. NAC, a ROS scavenger, reduced the nuclear translocation of ZKSCAN3 and sequentially improved ALP function in MPP-treated SN4741 cells. SRT2104, a SIRT1 activator, attenuated impairment of ALP in MPP-treated SN47417 cells through decreasing nuclear accumulation of ZKSCAN3 and protected dopaminergic neurons from MPTP injury. Moreover, SRT2104 relieved impairment in locomotor activities and coordination skills upon treatment of MPTP in C57/BL6J mice through behavior tests including rotarod, pole climbing and grid. Furthermore, ZKSCAN3 was a novel substrate of SIRT1 which was deacetylated at lysine 148 residues by SIRT1. This subsequently facilitated the shuttling of ZKSCAN3 to the cytoplasm. Therefore, our study identifies a novel acetylation-dependent regulatory mechanism of nuclear translocation of ZKSCAN3. It results in autophagy-lysosomal dysfunction and then leads to DA neuronal death in MPTP/MPP model of PD.
线粒体功能障碍、氧化应激和错误折叠蛋白聚集与自噬-溶酶体失调有关，并有助于帕金森病（PD）的发病机制。转录抑制剂 ZKSCAN3 在自噬和溶酶体发生中起着至关重要的作用。然而，ZKSCAN3 在 ALP 缺陷中的作用和修饰，以及与 PD 发病机制相关的分子机制仍不清楚。在这项研究中，我们证明了 MPP 暴露产生的细胞活性氧（ROS）和由此产生的氧化损伤被 SIRT1-ZKSCAN3 途径诱导所抵消。在这里，我们显示了核 ZKSCAN3 在 MPTP 处理的小鼠和 MPP 处理的 SN4741 细胞的腹侧中脑中显著增加。ZKSCAN3 的敲低减轻了 MPP 诱导的 ALP 缺陷、酪氨酸羟化酶（TH）下降和神经元死亡。ROS 清除剂 NAC 减少了 MPP 处理的 SN4741 细胞中 ZKSCAN3 的核易位，并依次改善了 ALP 功能。SIRT1 激活剂 SRT2104 通过减少核内 ZKSCAN3 的积累，减轻了 MPP 处理的 SN47417 细胞中 ALP 的损伤，并通过行为测试（包括转棒、爬杆和网格）保护 C57/BL6J 小鼠免受 MPTP 损伤。此外，SRT2104 通过行为测试（包括转棒、爬杆和网格）缓解了 MPTP 处理后 C57/BL6J 小鼠的运动活动和协调技能障碍。此外，ZKSCAN3 是 SIRT1 的一种新型底物，其赖氨酸 148 残基被 SIRT1 去乙酰化。这随后促进了 ZKSCAN3 向细胞质的易位。因此，我们的研究确定了 ZKSCAN3 核易位的一种新型依赖于乙酰化的调节机制。它导致自噬-溶酶体功能障碍，然后导致 MPTP/MPP 帕金森病模型中的 DA 神经元死亡。
