Drosophila notal bristle as a novel assessment tool for pathogenic study of Tau toxicity and screening of therapeutic compounds

Biochemical and Biophysical Research Communications
Po-An YehMing-Tsan Su

Abstract

To elucidate the Tau gain-of-toxicity functional mechanism and to search for potential treatments, we overexpressed human Tau variants (hTau) in the dorsal mesothorax (notum) of Drosophila. Overexpression of Tau variants caused loss of notal bristles, and the phenotype was used for evaluating toxicity of ectopic Tau. The bristle loss phenotype was found to be highly associated with the toxicity of hyperphosphoryled Tau in flies. We have shown that the bristle loss phenotype can be rescued either by reducing Glycogen synthase kinase 3beta (GSK3beta)/Shaggy (Sgg) activity or overexpressing Bbeta2 regulatory subunits of PP2A. Elevated expression of the Drosophila Bbeta2 homolog, Twins (Tws), also alleviated neuritic dystrophy of the dorsal arborization (da) neuron caused by Tau aggregation. Additionally, lowering endogenous Tau dosage was beneficial as it ameliorated the bristle loss phenotype. Finally, the bristle loss phenotype was used to evaluate the efficacy of potential therapeutic compounds. The GSK3beta inhibitor, alsterpaullone, was found to suppress toxicity of Tau in a concentration-dependent manner. The notum of Drosophila, thus, provides a new tool and insights into Tau-induced toxicity. It could also potentially assi...Continue Reading

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Citations

Feb 13, 2013·Molecular Psychiatry·J ChapuisUNKNOWN GERAD consortium
Jun 28, 2011·Human Molecular Genetics·Yasmina Talmat-AmarMarie-Laure Parmentier
Aug 20, 2010·International Journal of Alzheimer's Disease·Thorsten KoechlingJesus Avila
Jun 16, 2012·International Journal of Alzheimer's Disease·Marc GistelinckPierre Dourlen
Jan 22, 2019·Expert Opinion on Drug Discovery·Katerina PapanikolopoulouEfthimios Skoulakis
Jun 18, 2011·Molecular Neurobiology·Katerina Papanikolopoulou, Efthimios M C Skoulakis

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