RESUMEN
Parkinson's disease (PD) is a severe neurodegenerative disease associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although its pathogenesis remains unclear, microglia-mediated neuroinflammation significantly contributes to the development of PD. Here we showed that the sine oculis homeobox (SIX) homologue family transcription factors SIX2 exerted significant effects on neuroinflammation. The SIX2 protein, which is silenced during development, was reactivated in lipopolysaccharide (LPS)-treated microglia. The reactivated SIX2 in microglia mitigated the LPS induced inflammatory effects, and then reduced the toxic effect of conditioned media (CM) of microglia on co-cultured MES23.5 DA cells. Using the LPS-stimulated Cx3cr1-CreERT2 mouse model, we also demonstrated that the highly-expressed SIX2 in microglia obviously attenuated neuroinflammation and protected the DA neurons in SN. Further RNA-Seq analysis on the inflammatory activated microglia revealed that the SIX2 exerted these effects via up-regulating the FXYD domain containing ion transport regulator 2 (FXYD2). Taken together, our study demonstrated that SIX2 was an endogenous anti-inflammatory factor in microglia, and it exerted anti-neuroinflammatory effects by regulating the expression of FXYD2, which provides new ideas for anti-neuroinflammation in PD.
Asunto(s)
Proteínas de Homeodominio , Lipopolisacáridos , Microglía , Enfermedades Neuroinflamatorias , Regulación hacia Arriba , Animales , Ratones , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Inflamación/metabolismo , Inflamación/inducido químicamente , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Enfermedades Neuroinflamatorias/metabolismo , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
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.
