Transduced Tat-PRAS40 prevents dopaminergic neuronal cell death through ROS inhibition and interaction with 14-3-3σ protein

Won Sik Eum; Dae Won Kim; Eun Ji Yeo; Hyeon Ji Yeo; Yeon Joo Choi; Hyun Ju Cha; Jinseu Park; Kyu Hyung Han; Duk-Soo Kim; Yeon Hee Yu; Sung-Woo Cho; Oh-Shin Kwon; Yong-Jun Cho; Min Jea Shin; Soo Young Choi

doi:10.1016/j.freeradbiomed.2021.06.026

Transduced Tat-PRAS40 prevents dopaminergic neuronal cell death through ROS inhibition and interaction with 14-3-3σ protein

Free Radic Biol Med. 2021 Aug 20:172:418-429. doi: 10.1016/j.freeradbiomed.2021.06.026. Epub 2021 Jun 25.

Authors

Won Sik Eum¹, Dae Won Kim², Eun Ji Yeo¹, Hyeon Ji Yeo¹, Yeon Joo Choi¹, Hyun Ju Cha¹, Jinseu Park¹, Kyu Hyung Han¹, Duk-Soo Kim³, Yeon Hee Yu³, Sung-Woo Cho⁴, Oh-Shin Kwon⁵, Yong-Jun Cho⁶, Min Jea Shin⁷, Soo Young Choi⁸

Affiliations

¹ Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea.
² Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangneung-Wonju National University, Kangneung, 25457, South Korea.
³ Department of Anatomy and BK21 FOUR Project, College of Medicine, Soonchunhyang University, Cheonan, 31538, South Korea.
⁴ Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
⁵ School of Life Sciences, College of Natural Sciences Kyungpook National University, Taegu, 41566, South Korea.
⁶ Department of Neurosurgery, Hallym University Medical Center, Chuncheon, 24253, South Korea.
⁷ Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea. Electronic address: [email protected].
⁸ Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea. Electronic address: [email protected].

PMID: 34175438
DOI: 10.1016/j.freeradbiomed.2021.06.026

Abstract

Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and activated mTORC1 plays important roles for cellular survival in response to oxidative stress. However, the roles of PRAS40 in dopaminergic neuronal cell death have not yet been examined. Here, we examined the roles of Tat-PRAS40 in MPP⁺- and MPTP-induced dopaminergic neuronal cell death. Our results showed that Tat-PRAS40 effectively transduced into SH-SY5Y cells and inhibited DNA damage, ROS generation, and apoptotic signaling in MPP⁺-induced SH-SY5Y cells. Further, these protective mechanisms of Tat-PRAS40 protein display through phosphorylation of Tat-PRAS40, Akt and direct interaction with 14-3-3σ protein, but not via the mTOR-dependent signaling pathway. In a Parkinson's disease animal model, Tat-PRAS40 transduced into dopaminergic neurons in mouse brain and significantly protected against dopaminergic cell death by phosphorylation of Tat-PRAS40, Akt and interaction with 14-3-3σ protein. In this study, we demonstrated for the first time that Tat-PRAS40 directly protects against dopaminergic neuronal cell death. These results indicate that Tat-PRAS40 may provide a useful therapeutic agent against oxidative stress-induced dopaminergic neuronal cell death, which causes diseases such as PD.

Keywords: Dopaminergic neurons; Oxidative stress; Parkinson’s disease; Protein therapy; Tat-PRAS40.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cell Death
Dopaminergic Neurons*
Mice
Oxidative Stress*
Reactive Oxygen Species

Substances

Reactive Oxygen Species