Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder, characterized genetically by autosomal dominant inheritance, clinically by behavioral abnormalities and parkinson ism, and neuropathologically by tauopathy. Linkage analyses of affected fam ilies have led to identification of several exonic and intronic mutations i n the tau gene. In this study, we analyzed molecular species of tau in the soluble and insoluble fractions of brain affected by the FTDP-17 R406W muta tion. Protein chemical analysis and Western blotting using site-specific an tibodies indicated that almost equal amounts of wild-type and mutant tau we re present in the Sarkosyl-insoluble fraction of the R406W brain. Consisten t with this, wild-type and mutant tau colocalized in neurofibrillary tangle s in the frontal cortex and hippocampus of the R406W brain. In contrast to soluble R406W tau, which was less phosphorylated than soluble wild-type tau , the Sarkosyl-insoluble mutant tau was highly phosphorylated as well as th e insoluble wild-type tau.