title: Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity.
abstract: Aggregated and highly phosphorylated tau protein is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. We identified motifs of alternating polar and apolar amino acids within the microtubule-binding repeats of tau which were interrupted by small breaking stretches. Minimal mutation of these breaking sequences yielded a unique instantly aggregating tau mutant containing longer stretches of polar/apolar amino acids without losing its microtubule-binding capacity. These modifications produced rapid aggregation and cytotoxicity with accompanying occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270, AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and Alz50) in cells. Similar to pathological tau in the pretangle state, toxicity appeared to occur early without the requirement for extensive fibril formation. Thus, our mutant protein provides a novel platform for the investigation of the molecular mechanisms for toxicity and cellular behavior of pathologically aggregated tau proteins and the identification of its interaction partners.
authors.affiliation: Cell Biophysics Group, European Neuroscience Institute-Göttingen, Waldweg 33, 37073 Göttingen, Germany. ailiev@gwdg.de
authors.forename: Asparouh Iliev
authors.initials: AI
authors.lastname: Iliev
authors.forename: Sundar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Gertrude
authors.initials: G
authors.lastname: Bunt
authors.forename: Fred Silvester
authors.initials: FS
authors.lastname: Wouters
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D000939:Epitopes / Q000737:chemistry; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000737:chemistry*; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000939:Epitopes; C054369:MAPT protein, human; D016875:tau Proteins