Deacetylation of ZKSCAN3 by SIRT1 induces autophagy and protects SN4741 cells against MPP+-induced oxidative stress.

Abstract

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.

• Authors: Xian Wu, Yixian Ren, Yue Wen, Sixin Lu, Huihui Li, Honglin Yu, Wenjun Li, Fei Zou
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 181 Pg. 82-97 (03 2022) ISSN: 1873-4596 [Electronic] United States
• PMID: 35124181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Transcription Factors
• ZKSCAN3 protein, mouse
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Autophagy
• Dopaminergic Neurons (metabolism)
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• Oxidative Stress
• Sirtuin 1 (genetics, metabolism)
• Transcription Factors