Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells
Abstract This study investigated whether Toxoplasma gondii-derived dense granule protein 16 (GRA16) modulates tau protein to attenuate tau hyperphosphorylation and promotes autophagy to facilitate the removal of tau aggregates. HT-22 murine hippocampal neuronal cells were treated with thrombin to in...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-00271-4 |
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| author | Seung-Hwan Seo Do-Won Ham Ji-Eun Lee Eun-Hee Shin |
| author_facet | Seung-Hwan Seo Do-Won Ham Ji-Eun Lee Eun-Hee Shin |
| author_sort | Seung-Hwan Seo |
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| description | Abstract This study investigated whether Toxoplasma gondii-derived dense granule protein 16 (GRA16) modulates tau protein to attenuate tau hyperphosphorylation and promotes autophagy to facilitate the removal of tau aggregates. HT-22 murine hippocampal neuronal cells were treated with thrombin to induce rapid hyperphosphorylations and tau aggregation. Thrombin increased hyperphosphorylated tau protein levels and activated NF-κB, contributing to tau pathology and neuroinflammation. NF-κB activation increased apolipoprotein E (APOE) expression and decreased forkhead box O3A (FOXO3A) expression, a factor involved in autophagy regulation, consequently limiting the expression of autophagy-related genes directly regulated by FOXO3A. Meanwhile, in GRA16-transfected HT-22 cells treated with thrombin, GRA16 upregulated proteins involved in tau dephosphorylation but downregulated protein involved in tau phosphorylation. Moreover, GRA16 inhibited thrombin-induced NF-κB activation and increased FOXO3A levels, thereby enhancing the expression of autophagy-related genes, including those directly regulated by FOXO3A. GRA16 enhanced intracellular autophagic flux and inhibited tau hyperphosphorylations in thrombin-treated HT-22 cells, as evidenced by increased autophagic fluorescence and significant reductions in phosphorylated tau protein levels and fluorescence intensity. These findings suggest that GRA16 possesses therapeutic potential in tauopathies by enhancing tau dephosphorylation and autophagy-mediated tau clearance, establishing a conceptual foundation for developing new therapeutic approaches targeting tau pathology. |
| format | Article |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-ee15f7b89ff34e09a2e6044e23c9c9eb2025-08-20T02:34:06ZengNature PortfolioScientific Reports2045-23222025-05-0115111110.1038/s41598-025-00271-4Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cellsSeung-Hwan Seo0Do-Won Ham1Ji-Eun Lee2Eun-Hee Shin3Institute of Endemic Diseases, Medical Research Center, Seoul National UniversityDepartment of Tropical Medicine and Parasitology, Seoul National University College of MedicineDepartment of Tropical Medicine and Parasitology, Seoul National University College of MedicineInstitute of Endemic Diseases, Medical Research Center, Seoul National UniversityAbstract This study investigated whether Toxoplasma gondii-derived dense granule protein 16 (GRA16) modulates tau protein to attenuate tau hyperphosphorylation and promotes autophagy to facilitate the removal of tau aggregates. HT-22 murine hippocampal neuronal cells were treated with thrombin to induce rapid hyperphosphorylations and tau aggregation. Thrombin increased hyperphosphorylated tau protein levels and activated NF-κB, contributing to tau pathology and neuroinflammation. NF-κB activation increased apolipoprotein E (APOE) expression and decreased forkhead box O3A (FOXO3A) expression, a factor involved in autophagy regulation, consequently limiting the expression of autophagy-related genes directly regulated by FOXO3A. Meanwhile, in GRA16-transfected HT-22 cells treated with thrombin, GRA16 upregulated proteins involved in tau dephosphorylation but downregulated protein involved in tau phosphorylation. Moreover, GRA16 inhibited thrombin-induced NF-κB activation and increased FOXO3A levels, thereby enhancing the expression of autophagy-related genes, including those directly regulated by FOXO3A. GRA16 enhanced intracellular autophagic flux and inhibited tau hyperphosphorylations in thrombin-treated HT-22 cells, as evidenced by increased autophagic fluorescence and significant reductions in phosphorylated tau protein levels and fluorescence intensity. These findings suggest that GRA16 possesses therapeutic potential in tauopathies by enhancing tau dephosphorylation and autophagy-mediated tau clearance, establishing a conceptual foundation for developing new therapeutic approaches targeting tau pathology.https://doi.org/10.1038/s41598-025-00271-4AutophagyDense granule protein 16Hippocampal neuronal cellHyperphosphorylated TauTauopathyToxoplasma gondii |
| spellingShingle | Seung-Hwan Seo Do-Won Ham Ji-Eun Lee Eun-Hee Shin Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells Scientific Reports Autophagy Dense granule protein 16 Hippocampal neuronal cell Hyperphosphorylated Tau Tauopathy Toxoplasma gondii |
| title | Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells |
| title_full | Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells |
| title_fullStr | Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells |
| title_full_unstemmed | Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells |
| title_short | Toxoplasma GRA16 attenuates Tau hyperphosphorylation and enhances autophagy in thrombin-treated HT-22 hippocampal neuronal cells |
| title_sort | toxoplasma gra16 attenuates tau hyperphosphorylation and enhances autophagy in thrombin treated ht 22 hippocampal neuronal cells |
| topic | Autophagy Dense granule protein 16 Hippocampal neuronal cell Hyperphosphorylated Tau Tauopathy Toxoplasma gondii |
| url | https://doi.org/10.1038/s41598-025-00271-4 |
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