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Background <p>Tauopathies include a group of neurodegenerative disorders characterized by the aggregation of hyperphosphorylated tau protein in brain. An imbalance between tau-specific kinases and phosphatases has been implicated in the pathogenesis of tauopathies. The glycogen synthase kinase 3β (GSK3β), a key tau kinase, has emerged as a promising therapeutic target. We evaluated whether Disodium Cromoglycate (DSCG), a recognized GSK3β inhibitor, restricts pathogenic tau hyperphosphorylation and manifestation of associated phenotypes in <i>Drosophila.</i></p> Methods and Results <p>Human tauopathies in <i>Drosophila</i> was modelled by expressing pathogenic tau transgene in tissue specific manner by GAL4/UAS binary genetic tool. DSCG was administered orally to age-appropriate <i>Drosophila</i> of suitable genotypes at the specified concentrations. Preliminary screening, focused on establishing the relative ability to inhibit tau aggregation, identified 2 µM and 5 µM DSCG as the effective concentrations, which were then used in subsequent experiments. Various experiments such as brain sectioning, Mushroom body staining, cell death assay, behavioural assays etc. consistently suggested that effective dosages of DSCG efficiently restricts tau mediated neurodegeneration and the associated phenotypes. Immunostaining and western blot analysis subsequently suggested that DSCG treatment restricts tau hyperphosphorylation at the specific pathogenic site by increasing the inactive cellular pool of GSK3β in tau-expressing <i>Drosophila</i> tissues.</p> Conclusion <p>Our study suggests that DSCG treatment efficiently restricts pathogenic hyperphosphorylation of human tau and limits the manifestation of associated phenotypes in <i>Drosophila</i>. Given the functional conservation of GSK3β and its associated cellular mechanisms between humans and <i>Drosophila</i>, our findings emphasize the potential of DSCG as a therapeutic strategy for tauopathies.</p>

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Disodium cromoglycate restricts human tau hyperphosphorylation and manifestation of associated phenotypes by inhibiting GSK3β activity in Drosophila disease models

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Barasa Rani Kalita,
  • Surajit Sarkar

摘要

Background

Tauopathies include a group of neurodegenerative disorders characterized by the aggregation of hyperphosphorylated tau protein in brain. An imbalance between tau-specific kinases and phosphatases has been implicated in the pathogenesis of tauopathies. The glycogen synthase kinase 3β (GSK3β), a key tau kinase, has emerged as a promising therapeutic target. We evaluated whether Disodium Cromoglycate (DSCG), a recognized GSK3β inhibitor, restricts pathogenic tau hyperphosphorylation and manifestation of associated phenotypes in Drosophila.

Methods and Results

Human tauopathies in Drosophila was modelled by expressing pathogenic tau transgene in tissue specific manner by GAL4/UAS binary genetic tool. DSCG was administered orally to age-appropriate Drosophila of suitable genotypes at the specified concentrations. Preliminary screening, focused on establishing the relative ability to inhibit tau aggregation, identified 2 µM and 5 µM DSCG as the effective concentrations, which were then used in subsequent experiments. Various experiments such as brain sectioning, Mushroom body staining, cell death assay, behavioural assays etc. consistently suggested that effective dosages of DSCG efficiently restricts tau mediated neurodegeneration and the associated phenotypes. Immunostaining and western blot analysis subsequently suggested that DSCG treatment restricts tau hyperphosphorylation at the specific pathogenic site by increasing the inactive cellular pool of GSK3β in tau-expressing Drosophila tissues.

Conclusion

Our study suggests that DSCG treatment efficiently restricts pathogenic hyperphosphorylation of human tau and limits the manifestation of associated phenotypes in Drosophila. Given the functional conservation of GSK3β and its associated cellular mechanisms between humans and Drosophila, our findings emphasize the potential of DSCG as a therapeutic strategy for tauopathies.