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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
Published on: September 6, 2024
Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1
Can-Tang Zhang1, Deng-Li Qin2, Xia-Yin Cao2
1Department of Respiratory and Critical Care, the Affiliated Hospital of 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.
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