Article,

Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity

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J Biol Chem, 281 (48): 37195-204 (December 2006)Iliev, Asparouh Iliev Ganesan, Sundar Bunt, Gertrude Wouters, Fred Silvester Research Support, Non-U.S. Gov't United States The Journal of biological chemistry J Biol Chem. 2006 Dec 1;281(48):37195-204. Epub 2006 Sep 27..

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.

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