Abstract
SummaryHyperphosphorylation 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.
Highlights
The tauopathies are a group of neurodegenerative diseases characterised by the accumulation of intra-neural aggregates of the microtubule-associated protein, Tau
Several groups have used the Drosophila visual system as an in vivo model to examine how the toxicity of Tau varies with phosphorylation status
We have examined the importance of human kinases in modulating Tau toxicity in vivo
Summary
The tauopathies are a group of neurodegenerative diseases characterised by the accumulation of intra-neural aggregates of the microtubule-associated protein, Tau. Additional properties of Tau have been identified, including an ability to bundle actin filaments, and multiple Tau-binding partners have been identified, including tyrosine kinases. Together, these have led to the suggestion that Tau may act as a signalling scaffold (reviewed by Morris et al, 2011). The functions of Tau may be regulated both by alternative splicing (six isoforms are expressed in the human CNS) and through a multitude of post-translational modifications These include multiple phosphorylation and acetylation events, glycosylation, ubiquitylation and sumolyation amongst others (reviewed by Martin et al, 2011). In Drosophila both TauAP and TauS11A forms, with 14 or 11 Ser/Thr sites mutated to alanine
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
