Tau pathology in a family with dementia and a P301L mutation in tau

Familial forms of frontotemporal dementia and parkinsonism linked to chromo some 17 (FTDP-17) have recently been associated with coding region and intr onic mutations in the tau gene. Here we report our findings on 2 affected s iblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive d ementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of b asal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene re vealed a C to T transition at codon 301, resulting in a Pro to Leu substitu tion. Widespread neuronal and glial inclusions, neuropil threads, and astro cytic plaques similar to those seen in corticobasal degeneration were label ed with a battery of antibodies to phosphorylation-dependent and phosphoryl ation-independent epitopes spanning the entire tau sequence. Isolated tau f ilaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble t au exhibited ? major bands of 64 and 68 kDa and a minor 72 kDa band, simila r to the pattern seen in a Familial tauopathy associated with an intronic t au mutation. These pathological tau bands predominantly contained the subse t of tau isoforms with 4 microtubule-binding repeats selectively affected b y the P301L missense mutation. Our findings emphasize the phenotypic and ge netic heterogeneity of tauopathies and highlight intriguing links between F TDP-17 and other neurodegenerative diseases.