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

被引:83
作者
Goedert, M
Satumtira, S
Jakes, R
Smith, MJ
Kamibayashi, C
White, CL
Sontag, E
机构
[1] Univ Texas, SW Med Ctr, Dept Pathol, Neuropathol Lab, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX USA
[3] MRC, Mol Biol Lab, Cambridge CB2 2QH, England
关键词
protein phosphatase 2A; frontotemporal dementia and parkinsonism; linked to chromosome 17; frontotemporal dementia; tau mutations;
D O I
10.1046/j.1471-4159.2000.0752155.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 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 phosphatase in vivo. Using in vitro assays, we show here that the FTDP-17 mutations G272V, Delta K280, P301L, P301S, S305N, V337M, G389R, and R406W inhibit by 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 K280, 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.
引用
收藏
页码:2155 / 2162
页数:8
相关论文
共 45 条
[1]   STRUCTURE AND NOVEL EXONS OF THE HUMAN-TAU GENE [J].
ANDREADIS, A ;
BROWN, WM ;
KOSIK, KS .
BIOCHEMISTRY, 1992, 31 (43) :10626-10633
[2]   ABNORMAL TAU-PHOSPHORYLATION AT SER(396) IN ALZHEIMERS-DISEASE RECAPITULATES DEVELOPMENT AND CONTRIBUTES TO REDUCED MICROTUBULE-BINDING [J].
BRAMBLETT, GT ;
GOEDERT, M ;
JAKES, R ;
MERRICK, SE ;
TROJANOWSKI, JQ ;
LEE, VMY .
NEURON, 1993, 10 (06) :1089-1099
[3]   Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau [J].
Bugiani, O ;
Murrell, JR ;
Giaccone, G ;
Hasegawa, M ;
Ghigo, G ;
Tabaton, M ;
Morbin, M ;
Primavera, A ;
Carella, F ;
Solaro, C ;
Grisoli, M ;
Savoiardo, M ;
Spillantini, MG ;
Tagliavini, F ;
Goedert, M ;
Ghetti, B .
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 1999, 58 (06) :667-677
[4]   The structural basis of monoclonal antibody Alz50's selectivity for Alzheimer's disease pathology [J].
Carmel, G ;
Mager, EM ;
Binder, LI ;
Kuret, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (51) :32789-32795
[5]   Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17 [J].
Clark, LN ;
Poorkaj, P ;
Wszolek, Z ;
Geschwind, DH ;
Nasreddine, ZS ;
Miller, B ;
Li, D ;
Payami, H ;
Awert, F ;
Markopoulou, K ;
Andreadis, A ;
D'Souza, I ;
Lee, VMY ;
Reed, L ;
Trojanowski, JQ ;
Zhukareva, V ;
Bird, T ;
Schellenberg, G ;
Wilhelmsen, KC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) :13103-13107
[6]   Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements [J].
D'Souza, I ;
Poorkaj, P ;
Hong, M ;
Nochlin, D ;
Lee, VMY ;
Bird, TD ;
Schellenberg, GD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5598-5603
[7]   Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation [J].
Dayanandan, R ;
Van Slegtenhorst, M ;
Mack, TGA ;
Ko, L ;
Yen, SH ;
Leroy, K ;
Brion, JP ;
Anderton, BH ;
Hutton, M ;
Lovestone, S .
FEBS LETTERS, 1999, 446 (2-3) :228-232
[8]   Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments [J].
Goedert, M ;
Jakes, R ;
Crowther, RA .
FEBS LETTERS, 1999, 450 (03) :306-311
[9]  
GOEDERT M, 1995, J NEUROCHEM, V65, P2804
[10]   CLONING AND SEQUENCING OF THE CDNA-ENCODING AN ISOFORM OF MICROTUBULE-ASSOCIATED PROTEIN TAU CONTAINING 4 TANDEM REPEATS - DIFFERENTIAL EXPRESSION OF TAU PROTEIN MESSENGER-RNAS IN HUMAN-BRAIN [J].
GOEDERT, M ;
SPILLANTINI, MG ;
POTIER, MC ;
ULRICH, J ;
CROWTHER, RA .
EMBO JOURNAL, 1989, 8 (02) :393-399