Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression

Can-Tang Zhang; Deng-Li Qin; Xia-Yin Cao; Jia-Shuo Kan; Xin-Xing Huang; Dian-Shuai Gao; Jin Gao

doi:10.1016/j.isci.2023.107049

Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression

iScience. 2023 Jun 7;26(7):107049. doi: 10.1016/j.isci.2023.107049. eCollection 2023 Jul 21.

Authors

Can-Tang Zhang¹, Deng-Li Qin², Xia-Yin Cao², Jia-Shuo Kan², Xin-Xing Huang², Dian-Shuai Gao², Jin Gao²

Affiliations

¹ Department of Respiratory and Critical Care, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
² Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). We recently reported that Six2 could reverse the degeneration of DA neurons in a dephosphorylation state. Here we further identified that Eya1 was the phosphatase of Six2 that could dephosphorylate the tyrosine 129 (Y129) site by forming a complex with Six2 in damaged DA cells. Dephosphorylated Six2 then translocates from the cytoplasm to the nucleus. Using ChIP-qPCR and dual luciferase assay, we found that dephosphorylated Six2 down-regulates TEA domain1 (Tead1) expression, thus inhibiting 6-hydroxydopamine (6-OHDA)-induced apoptosis in DA cells. Furthermore, we showed Six2Y129F/Tead1 signaling could protect against the loss of SNpc tyrosine hydroxylase-positive (TH⁺) cells and improve motor function in PD model rats. Our results demonstrate a dephosphorylation-dependent mechanism of Six2 that restores the degeneration of DA neurons, which could represent a potential therapeutic target for PD.

Keywords: Biochemistry; Molecular biology; Neuroscience.