Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity.
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.
Iliev
Asparouh Iliev
AI
Cell Biophysics Group, European Neuroscience Institute-Göttingen, Waldweg 33, 37073 Göttingen, Germany. ailiev@gwdg.de
Ganesan
Sundar
S
Bunt
Gertrude
G
Wouters
Fred Silvester
FS
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*
D000939:Epitopes; C054369:MAPT protein, human; D016875:tau Proteins