The so referred to as rough eye phenotype correlates together with the reduction of retinal cells together with photore ceptors Thorough examination revealed that Tau overexpression brought on degeneration of photoreceptor axons, evident from the visual appeal of vacuoles from the medulla, the projection target of photoreceptor axons Such REPs are regularly used to display for genetic interactions In this kind of an strategy the fly ortholog of glycogen synthase kinase 3B was recognized to interfere with Tau induced toxicity. Interestingly, the Tau induced REP was suppressed in a GSK3B deficient background and enhanced by GSK3B overexpression Detailed analysis showed that overexpression of GSK3B strongly enhanced pathogenic phosphorylation of Tau In an effort to investigate the part of Tau phosphorylation and toxicity in far more detail, various Tau variants with altered phosphorylation web sites were produced Chatterjee et al.
made Screening Library solubility fly lines expressing phosphoryl ation resistant Tau variants by exchanging two or eleven putative serine threonine phosphorylation internet sites with neutral alanine. These mutations prevented phos phorylation by protease activated receptor 1 and GSK3B, respectively This allowed a thorough investi gation of many Tau kinases in ailment connected processes just like internet site specific phosphorylation and alterations in MT binding properties of Tau Interestingly, REP enhancement induced by overexpression of GSK3B was significantly less pronounced inside the TauS2A expressing fly pared to your wild variety Tau expressing fly though immunoblotting applying phosphorylation webpage precise Tau antibodies showed a larger degree of Tau phosphorylation. In contrast, TauS11A was resistant to GSK3B phosphorylation though GSK3B overexpression enhanced the TauS2A induced REP severity.
Furthermore, neither Tau aggregation nor MT binding properties persistently correlated with REP These results uncouple Tau toxicity from sole phosphoryl ation and indicate Tau toxicity is partially independent of its phosphorylation state. Additionally, Iijima Ando et al. produced an additional phosphorylation resistant Tau variant TauS262A AT9283 Retinal coexpression of wild variety human Tau and DNA damage activated checkpoint kinase 2 resulted in enrich ment with the REP. In contrast, coexpression of Chk2 and TauS262A had no impact on eye surface integrity To determine the contribution of unique phosphoryl ation web pages to Tau toxicity, Steinhilb et al. developed novel Tau transgenes By changing serines of several illness associated phosphorylation web sites with alanine they developed a phosphorylation resistant variant and by changing serines with glutamines they mimicked a hyperphosphorylated state of Tau The conse quences are amelioration of Tau toxicity in flies expressing phospho deficient Tau variant TauAP and exacerbation of Tau toxicity in flies expressing the phospho mimetic Tau variant TauE14 However, mutation of individual serines in the respective phosphorylation internet sites did not consequence inside a clear modulation of Tau toxicity indicating that many sites perform in concert to confer to Tau toxicity Folwell and co workers analyzed con itant expression of AB42 and Tau in flies.