title: Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo.
abstract: Dysfunction and accumulation of the microtubule-associated human Tau (hTau) protein into intraneuronal aggregates is observed in many neurodegenerative disorders including Alzheimer's disease (AD). Reversible lysine acetylation has recently emerged as a post-translational modification that may play an important role in the modulation of hTau pathology. Acetylated hTau species have been observed within hTau aggregates in human AD brains and multi-acetylation of hTau in vitro regulates its propensity to aggregate. However, whether lysine acetylation at position 280 (K280) modulates hTau-induced toxicity in vivo is unknown. We generated new Drosophila transgenic models of hTau pathology to evaluate the contribution of K280 acetylation to hTau toxicity, by analysing the respective toxicity of pseudo-acetylated (K280Q) and pseudo-de-acetylated (K280R) mutant forms of hTau. We observed that mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. In addition, modulation of K280 influenced total hTau levels and phosphorylation without changing hTau solubility. Altogether, our results indicate that pseudo-acetylation of the single K280 residue is sufficient to exacerbate hTau neurotoxicity in vivo, suggesting that acetylated K280-hTau species contribute to the pathological events leading to neurodegeneration in AD.
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany; CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, 50931 Cologne, Germany.
authors.forename: Marianna Karina
authors.initials: MK
authors.lastname: Gorsky
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany; CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, 50931 Cologne, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Burnouf
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany; CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, 50931 Cologne, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dols
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany; CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Hamburg.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany; CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, 50931 Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000107:Acetylation; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D066263:Protein Aggregation, Pathological; D011499:Protein Processing, Post-Translational; D016875:tau Proteins / Q000378:metabolism / Q000633:toxicity*
chemical_list: C054369:MAPT protein, human; D009498:Neurotoxins; D016875:tau Proteins; D008239:Lysine