Competition for microtubule-binding with dual expression of tau missense and splice isoforms

How tau mutations lead to neurodegeneration is unknown but may be related t o altered microtubule binding properties of mutant tau protein. The tendenc y for the mutations to cluster around the microtubule-binding domain of tau or to alter the ratios of those splice isoforms that affect binding suppor ts the view that the tau/microtubule interaction is critical and finely reg ulated. In cells transfected with both mutant and wild-type tau isoforms fu sed to either yellow fluorescent protein or cyan fluorescent protein we can observe tau fusion proteins that differ by a single amino acid or by the i nclusion or exclusion of exon 10. With coexpression of mutant and wild-type tau, the mutant isoform appears diffuse throughout the cytoplasm; however, when mutant tau is expressed alone, it appears mostly bound to the microtu bules. Dual imaging of the three- and four-repeat tau isoforms indicated th at the expression of few-repeat tau displaced three-repeat tau from the mic rotubules. These results suggest that altered kinetic competition among the isoforms for microtubule binding could be a disease precipitant.