PMID- 11032905
OWN - NLM
STAT- MEDLINE
DCOM- 20001109
LR  - 20190630
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 75
IP  - 5
DP  - 2000 Nov
TI  - Reduced binding of protein phosphatase 2A to tau protein with frontotemporal 
      dementia and parkinsonism linked to chromosome 17 mutations.
PG  - 2155-62
AB  - 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.
FAU - Goedert, M
AU  - Goedert M
AD  - Medical Research Council Laboratory of Molecular Biology, Cambridge, England.
FAU - Satumtira, S
AU  - Satumtira S
FAU - Jakes, R
AU  - Jakes R
FAU - Smith, M J
AU  - Smith MJ
FAU - Kamibayashi, C
AU  - Kamibayashi C
FAU - White, C L 3rd
AU  - White CL 3rd
FAU - Sontag, E
AU  - Sontag E
LA  - eng
GR  - AG12300/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Cell Extracts)
RN  - 0 (MAPT protein, human)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (tau Proteins)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - Brain Chemistry
MH  - Cell Extracts/chemistry
MH  - Cells, Cultured
MH  - Chromosomes, Human, Pair 17/*genetics
MH  - Dementia/*genetics
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Haplorhini
MH  - Humans
MH  - Immunoblotting
MH  - Mice
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Mutation/genetics
MH  - Parkinsonian Disorders/*genetics
MH  - Phosphoprotein Phosphatases/genetics/*metabolism
MH  - Precipitin Tests
MH  - Protein Binding/genetics
MH  - Protein Phosphatase 2
MH  - Rats
MH  - Transfection
MH  - tau Proteins/genetics/*metabolism
EDAT- 2000/10/18 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/10/18 11:00
PHST- 2000/10/18 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/10/18 11:00 [entrez]
AID - 10.1046/j.1471-4159.2000.0752155.x [doi]
PST - ppublish
SO  - J Neurochem. 2000 Nov;75(5):2155-62. doi: 10.1046/j.1471-4159.2000.0752155.x.