Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β
Summary 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 indi...
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doaj-4904fa645e094147818f971a452f62d32021-06-02T18:02:20ZengThe Company of BiologistsBiology Open2046-63902013-11-013111110.1242/bio.2013669220136692Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3βGiulia Povellato0Richard I. Tuxworth1Diane P. Hanger2Guy Tear3 MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, UK MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, UK Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, UK Summary 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.http://bio.biologists.org/content/3/1/1TauPhosphorylationGSK3βDrosophila |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giulia Povellato Richard I. Tuxworth Diane P. Hanger Guy Tear |
spellingShingle |
Giulia Povellato Richard I. Tuxworth Diane P. Hanger Guy Tear Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β Biology Open Tau Phosphorylation GSK3β Drosophila |
author_facet |
Giulia Povellato Richard I. Tuxworth Diane P. Hanger Guy Tear |
author_sort |
Giulia Povellato |
title |
Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β |
title_short |
Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β |
title_full |
Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β |
title_fullStr |
Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β |
title_full_unstemmed |
Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3β |
title_sort |
modification of the drosophila model of in vivo tau toxicity reveals protective phosphorylation by gsk3β |
publisher |
The Company of Biologists |
series |
Biology Open |
issn |
2046-6390 |
publishDate |
2013-11-01 |
description |
Summary
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. |
topic |
Tau Phosphorylation GSK3β Drosophila |
url |
http://bio.biologists.org/content/3/1/1 |
work_keys_str_mv |
AT giuliapovellato modificationofthedrosophilamodelofinvivotautoxicityrevealsprotectivephosphorylationbygsk3b AT richardituxworth modificationofthedrosophilamodelofinvivotautoxicityrevealsprotectivephosphorylationbygsk3b AT dianephanger modificationofthedrosophilamodelofinvivotautoxicityrevealsprotectivephosphorylationbygsk3b AT guytear modificationofthedrosophilamodelofinvivotautoxicityrevealsprotectivephosphorylationbygsk3b |
_version_ |
1721402395372552192 |