[Molecular analysis of tau deposited in the FTDP-17 brain]

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 parkinsonism, and neuropathologically by tauopathy. Linkage analyses of affected families have led to identification of many exonic and intronic mutations in the tau gene. Using site-specific antibodies that distinguish between wild-type and mutant tau, we analyzed molecular species of tau in the soluble and insoluble fractions of the brain affected by two FTDP-17 mutations, P301L and R406W. Western blotting showed that mutant tau was preferentially deposited in the Sarkosyl-insoluble fraction of the P301L brain. Consistent with this, immunocytochemistry showed that intraneuronal tau deposits consisted exclusively of mutant tau. On the other hand, the protein levels of mutant tau in the soluble fraction were selectively decreased despite no detectable decrease in its mRNA levels. In contrast, almost equal amounts of wild-type and mutant tau were present in the Sarkosyl-insoluble fraction of the R406W brain and their levels in the soluble fraction did not differ from each other. Wild-type and mutant tau colocalized in neurofibrillary tangles in the frontotemporal cortices. In contrast to soluble R406W tau, which was less phosphorylated than soluble wild-type tau. Sarkosyl-insoluble R406W tau was highly phosphorylated to a similar extent as insoluble wild-type tau.