Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients

Mutations in the gene for the microtubule-associated protein tau are associ ated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, u sing polyclonal antibodies specific for the P301L point mutation and its no rmal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both pr esent in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fracti on of frontal and temporal cortex the overall ratio of 3-repeat versus 4-re peat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cle avage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase exp eriments. This is the first direct evidence using patient material that sho ws a selective aggregation of mutant tau protein resulting in sarkosyl-inso luble deposits and the specific depletion of mutated tau protein in the sol uble fraction.