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

M. Goedert, S. Satumtira, R. Jakes, M. J. Smith, C. Kamibayashi, C. L. White, E. Sontag

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

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 ABαC, 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, ΔK280, P301L, P301S, S305N, V337M, G389R, and R406W inhibit by˜20-95% the binding of recombinant three-repeat and four-repeat tau isoforms to the ABαC holoenzyme and the AC core enzyme of PP2A. Reduction in binding was maximal for tau proteins with the G272V, ΔK280, 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.

Original languageEnglish (US)
Pages (from-to)2155-2162
Number of pages8
JournalJournal of Neurochemistry
Volume75
Issue number5
DOIs
StatePublished - Jan 1 2000

Keywords

  • Frontotemporal dementia
  • Frontotemporal dementia and parkinsonism linked to chromosome 17
  • Protein phosphatase 2A
  • Tau mutations

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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