NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

Author:

Yang Tingting1,Xu Yongjie2,Zhu Liying1,Xu Wen2,Huang Changyudong1,Li Haizhi3,Wei Sijia1,Wang Shuang1,Zhang Yiqiong1,Yang Huiru2,Duan Yunfeng1,Li Xing4,Zhao Shuyun3,Tang Lei5,Pan Wei2

Affiliation:

1. School of clinical laboratory science, Guizhou Medical University

2. Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University

3. Center for Reproductive Medicine, Affiliated Hospital of Guizhou Medical University,

4. School of Basic Medical Science, Guizhou University of Traditional Chinese Medicine

5. School of Basic Medical Science, Guizhou Medical University

Abstract

Abstract Diabetes-associated cognitive dysfunction(DACD) is one of the neurological complications of diabetes, and it mainly involves the hippocampal region of the brain and affects the learning and memory functions of the body. There are many studies on the pathogenesis of DACD, but there is a lack of in-depth studies on the underlying molecular mechanism, which poses a great challenge to drug development. In this study, we focused on the molecular mechanism by which signal transduction by the glycine transporter GlyT1 participates in the development of DACD and systematically elucidated the processes of synaptic plasticity and apoptosis in hippocampal neurons. The results showed that when neurons were exposed to a high-glucose environment, low levels of GlyT1 inhibited the activation of the PI3K/AKT/mTOR pathway to promote neuronal apoptosis; additionally, GlyT1 regulated NMDR expression to regulate glycine concentrations in order to reduce synaptic plasticity. The transcription factor Sp1 bound to the GlyT1 promoter region and regulated GlyT1 expression, so we explored whether Sp1 expression was regulated by the protease-ubiquitin system, resulting in decreased Sp1 levels.In conclusion, In conclusion, our study systematically demonstrated the biological function and molecular mechanism by which GlyT1 participates in DACD development, elucidated the upstream and downstream mechanisms of GlyT1 regulation, provided reliable molecular targets for DACD treatment, and enhanced the understanding of the mechanism underlying DACD development.

Publisher

Research Square Platform LLC

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