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Povellato G, Tuxworth RI, Hanger DP, et al. Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β. Biol Open. 2014;3(1):1-11doi: 10.1242/bio.20136692.
Povellato, G., Tuxworth, R. I., Hanger, D. P., & Tear, G. (2014). Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β. Biology open, 3(1), 1-11. https://doi.org/10.1242/bio.20136692
Povellato, Giulia, et al. "Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β." Biology open vol. 3,1 (2014): 1-11. doi: https://doi.org/10.1242/bio.20136692
Povellato G, Tuxworth RI, Hanger DP, Tear G. Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β. Biol Open. 2014 Jan 15;3(1):1-11. doi: 10.1242/bio.20136692. PMID: 24429107; PMCID: PMC3892155.
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Biol Open. 2014 Jan 15;3(1):1-11. doi: 10.1242/bio.20136692.

Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β.

Biology open

Giulia Povellato, Richard I Tuxworth, Diane P Hanger, Guy Tear

Affiliations

  1. MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, UK.

PMID: 24429107 PMCID: PMC3892155 DOI: 10.1242/bio.20136692

Abstract

Hyperphosphorylation of the microtubule associated protein, Tau, is the hallmark of a group of neurodegenerative disorders known as the tauopathies which includes Alzheimer's disease. Precisely how and why Tau phosphorylation is increased in disease is not fully understood, nor how individual sites modify Tau function. Several groups have used the Drosophila visual system as an in vivo model to examine how the toxicity of Tau varies with phosphorylation status. This system relies on overexpression of Tau from transgenes but is susceptible to position effects altering expression and activity of the transgenes. We have refined the system by eliminating position effects through the use of site-specific integration. By standardising Tau expression levels we have been able to compare directly the toxicity of different isoforms of Tau and Tau point mutants that abolish important phosphorylation events. We have also examined the importance of human kinases in modulating Tau toxicity in vivo. We were able to confirm that human GSK3β phosphorylates Tau and increases toxicity but, unexpectedly, we identified that preventing phosphorylation of Ser404 is a protective event. When phosphorylation at this site is prevented, Tau toxicity in the Drosophila visual system is increased in the presence of GSK3β. Our data suggest that not all phosphorylation events on Tau are associated with toxicity.

Keywords: Drosophila; GSK3β; Phosphorylation; Tau

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