Drosophila notal bristle as a novel assessment tool for pathogenic study of Tau toxicity and screening of therapeutic compounds.
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 assist in screening new drugs for possible therapeutic intervention.
Yeh
Po-An
PA
Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan, ROC.
Chien
Ju-Yi
JY
Chou
Chih-Chung
CC
Huang
Yu-Fen
YF
Tang
Chiou-Yang
CY
Wang
Hsiang-Yu
HY
Su
Ming-Tsan
MT
D000818:Animals; D030801:Animals, Genetically Modified; D001552:Benzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D001552:Benzazepines; D029721:Drosophila Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; C120793:alsterpaullone; D016875:tau Proteins; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D010749:Phosphoprotein Phosphatases; C079898:tws protein, Drosophila