Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations

Coding region and intronic mutations in the tau gene cause frontotemporal d ementia and parkinsonism linked to chromosome 17 (FTDP-17). We have previou sly reported that AB alpha C, a major form of protein phosphatase 2A (PP2A) in brain, binds tightly to tau protein in vitro and is a major tau phospha tase in vivo. Using in vitro assays, we show here that the FTDP-17 mutation s G272V, Delta K280, P301L, P301S, S305N, V337M, G389R, and R406W inhibit b y similar to 20-95% the binding of recombinant three-repeat and four-repeat tau isoforms to the AB alpha C holoenzyme and the AC core enzyme of PP2A. Reduction in binding was maximal for tau proteins with the G272V, Delta K28 0, and V337M mutations. We also show that tau protein can be specifically c oimmunoprecipitated with endogenous PP2A from both rat brain and transfecte d cell extracts. It is significant that, by using similar coimmunoprecipita tion assays, we show that all FTDP-17 mutations tested, including the N279K mutation, alter the ability of tau to associate with cellular PP2A. Taken together, these results indicate that FTDP-17 mutations induce a significan t decrease in the binding affinity of tau for PP2A in vivo. We propose that altered protein-protein interactions between PP2A and tau may contribute t o FTDP-17 pathogenesis.