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 dementia and parkinsonism linked to chromosome 17 (FTDP-17). We have previously reported that ABalphaC, a major form of protein phosphatase 2A (PP2A) in brain, binds tightly to tau protein in vitro and is a major tau phosphatase in vivo. Using in vitro assays, we show here that the FTDP-17 mutations G272V, DeltaK280, P301L, P301S, S305N, V337M, G389R, and R406W inhibit by approximately 20-95% the binding of recombinant three-repeat and four-repeat tau isoforms to the ABalphaC holoenzyme and the AC core enzyme of PP2A. Reduction in binding was maximal for tau proteins with the G272V, DeltaK280, and V337M mutations. We also show that tau protein can be specifically coimmunoprecipitated with endogenous PP2A from both rat brain and transfected cell extracts. It is significant that, by using similar coimmunoprecipitation 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 significant decrease in the binding affinity of tau for PP2A in vivo. We propose that altered protein-protein interactions between PP2A and tau may contribute to FTDP-17 pathogenesis.
Goedert
M
M
Medical Research Council Laboratory of Molecular Biology, Cambridge, England.
Satumtira
S
S
Jakes
R
R
Smith
M J
MJ
Kamibayashi
C
C
White
C L
CL
Sontag
E
E
D016475:3T3 Cells; D000818:Animals; D001923:Brain Chemistry; D002457:Cell Extracts / Q000737:chemistry; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003704:Dementia / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D000882:Haplorhini; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000235:genetics; D054648:Protein Phosphatase 2; D051381:Rats; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D002457:Cell Extracts; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2