2. Academic Validation
  3. Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression

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.
Can-Tang Zhang 1,  Deng-Li Qin 2,  Xia-Yin Cao 2,  Jia-Shuo Kan 2,  Xin-Xing Huang 2,  Dian-Shuai Gao 2,  Jin Gao 2
Affiliations

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.
PMID: 37534182 DOI: 10.1016/j.isci.2023.107049
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.

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