Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein.
Tau is a neuronal microtubule-associated protein involved in microtubules assembly and stabilization. Tauopathies, including Alzheimer's disease and fronto-temporal dementia with parkinsonism linked to chromosome 17, are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of abnormally and hyperphosphorylated Tau. Currently, the molecular mechanisms underlying Tau-mediated cellular toxicity remain elusive. To address the determinants of Tau neurotoxicity, we used Drosophila models of human tauopathies to study the microtubule-binding properties of human Tau proteins in vivo. We showed that, in contrast to endogenous Drosophila Tau, human Tau proteins bind very poorly to microtubules in Drosophila, and are mostly recovered as soluble cytosolic hyperphosphorylated species. This weak binding of human Tau to microtubules is neither because of microtubules saturation nor competition with endogenous Drosophila Tau, but clearly depends on its phosphorylation degree. We also reported that accumulation of cytosolic hyperphosphorylated forms of human Tau proteins correlates with human Tau-mediated neurodegeneration in flies, supporting the key role of soluble cytosolic hyperphosphorylated Tau proteins as toxic species in vivo.
Feuillette
Sébastien
S
Inserm U614, Rouen Institute for Medical Research, Faculty of Medicine, University of Rouen, Rouen Cedex, France.
Miguel
Laetitia
L
Frébourg
Thierry
T
Campion
Dominique
D
Lecourtois
Magalie
M
D000818:Animals; D030801:Animals, Genetically Modified; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009420:Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D012995:Solubility; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
D016875:tau Proteins