Protein phosphatase 2A, a key player in Alzheimer’s disease
Protein phosphatase 2A, a key player in Alzheimer’s disease
Rong LIU(), Qing TIAN
Department of Pathophysiology, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Protein phosphatase 2A (PP2A) is the predominant serine/threonine phosphatase in eukaryotic cells. In the brains of patients with Alzheimer’s disease (AD), decreased PP2A activities were observed, which is suggested to be involved in neurofibrillary tangle (NFT) formation, disturbed amyloid precursor protein (APP) secretion and neurodegeneration in AD brain. Based on our research and other previous findings, decreased PP2Ac level, decreased PP2A holoenzyme composition, increased level of PP2A inhibitors, increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation underlie PP2A inactivation in AD. β-amyloid (Aβ) over-production, estrogen deficiency and impaired homocysteine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons. Further studies are required to disclose the role of PP2A in Alzheimer’s disease.
Corresponding Author(s):
LIU Rong,Email:lilylizzy@yahoo.com.cn
引用本文:
. Protein phosphatase 2A, a key player in Alzheimer’s disease[J]. Frontiers of Medicine in China, 2009, 3(1): 8-12.
Rong LIU, Qing TIAN. Protein phosphatase 2A, a key player in Alzheimer’s disease. Front Med Chin, 2009, 3(1): 8-12.
Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signaling. Biochem J , 2001, 353(Pt 3): 417-439
2
Cohen P T W, BrewisN D, Hughes V, Mann D J. Protein serine/threonine phosphatases; an expanding family. FEBS Lett , 1990, 268(2): 355-359
3
Mumby M C, Russel K L, Garrard L J, Green D D. Cardiac contractile protein phosphatases. J Biol Chem , 1987, 262(13): 6257-6265
4
Agostinis P, Goris J, Pinna L A, Marchiori F, Perich J W, Meyer H E, Merlevede W. Synthetic peptides as model substrates for the study of the specificity of the polycation-stimulated protein phosphatases. Eur J Biochem , 1990, 189(2): 235-241
5
Grundke-Iqbal I, Iqbal K, Tung Y C, Quinlan M, Wisniewski H M, Binder L I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A , 1986, 83(13): 4913-4917
6
Grundke-Iqbal I, Iqbal K, Quinlan M, Tung Y C, Zaidi M S, Wisniewski H M. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem , 1986, 261(13): 6084-6089
7
Lee V M, Balin B J, Otvos L Jr, Trojanowski J Q. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science , 1991, 251(4994): 675-678
8
Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K. Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett , 1993, 325(3): 167-172
9
Liu F, Grundke-Iqbal I, Iqbal K, Gong C X. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci , 2005, 22(8): 1942-1950
10
Pei J J, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn R F. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol , 1999, 58(9): 1010-1019
11
Gong C X, Singh T J, Grundke-Iqbal I, Iqbal K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem , 1993, 61(3): 921-927
12
Gong C X, Shaikh S, Wang J Z, Zaidi T, Grundke-Iqbal I, Iqbal K. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem , 1995, 65(2): 732-738
13
Wang J Z, Gong C X, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and-2B. J Biol Chem , 1995, 270(9): 4854-4860
14
Sontag E, Nunbhakdi-Craig V, Sontag J M, Diaz-Arrastia R, Ogris E, Dayal S, Lentz S R, Arning E, Bottiglieri T. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci , 2007, 27(11): 2751-2759
15
Gong C X, Singh T J, Grundke-Iqbal I, Iqbal K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem , 1993, 61(3): 921-927
16
Gong C X, Shaikh S, Wang J Z, Zaidi T, Grundke-Iqbal I, Iqbal K. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem , 1995, 65(2): 732-738
18
Saito T, Ishiguro K, Uchida T, Miyamoto E, Kishimoto T, Hisanaga S. In situ dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons. FEBS Lett , 1995, 376(3): 238-242
19
Wang J Z, Grundke-Iqbal I, Iqbal K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res , 1996, 38(2): 200-208
20
Gong C X, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem , 2000, 275(8): 5535-5544
21
Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I. The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett , 1998, 426(2): 248-254
22
Sun L, Liu S Y, Zhou X W, Wang X C, Liu R, Wang Q, Wang J Z. Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience , 2003, 118(4): 1175-1182
23
Tian Q, Lin Z Q, Wang X C, Chen J, WangQ, Gong C X, Wang J Z. Injection of okadaic acid into the meynert nucleus basalis of rat brain induces decreased acetylcholine level and spatial memory deficit. Neuroscience , 2004, 126(2): 277-284
24
Kins S, Crameri A, Evans D R, Hemmings B A, Nitsch R M, Gotz J. Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem , 2001, 276(41): 38193-38200
25
Gandy S E, Caporaso G L, Buxbaum J D, de Cruz S O, Iverfeldt K, Nordstedt C, Suzuki T, Czernik A J, Nairn A C, Greengard P. Protein phosphorylation regulates relative utilization of processing pathways for Alzheimer beta/A4 amyloid precursor protein. Ann NY Acad Sci , 1993, 695(24): 117-121
26
da Cruz e Silva E F, da Cruz e Silva O A, Zaia C T, Greengard P. Inhibition of protein phosphatase 1 stimulates secretion of Alzheimer amyloid precursor protein. Mol Med , 1995, 1(5): 535-541
27
Holzer M, Bruckner M K, Beck M, Bigl V, Arendt T. Modulation of APP processing and secretion by okadaic acid in primary guinea pig neurons. J Neural Transm , 2000, 107(4): 451-461
28
Henriques A G, Domingues S C, Fardilha M, da Cruz e Silva E F, da Cruz e Silva O A. Sodium azide and 2-deoxy-D-glucose-induced cellular stress affects phosphorylation-dependent AbetaPP processing. J Alzheimers Dis , 2005, 7(3): 201-212
29
Buxbaum J D, Koo E H, Greengard P. Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc Natl Acad Sci USA , 1993, 90(19): 9195-9198
30
Arendt T, Holzer M, Fruth R, Bruckner M K, Gartner U. Phosphorylation of tau, Abeta formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A. Neurobiol Aging , 1998, 19(1): 3-13
31
Sun X, Cole G M, Chu T, Xia W, Galasko D, Yamaguchi H, Tanemura K, Frautschy S A, Takashima A. Intracellular Abeta is increased by okadaic acid exposure in transfected neuronal and non-neuronal cell lines. Neurobiol Aging , 2002, 23(2): 195-203
32
Ando S, Iijima K I, Elliott J I, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J Biol Chem , 2001, 276(43): 40353-40361
33
Phiel C J, Wilson C A, Lee V M, Klein P S. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature , 2003, 423(6938): 435-439
34
Pierrot N, Santos S F, Feyt C, Morel M, Brion J P, Octave J N. Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation. J Biol Chem , 2006, 281(52): 39907-39914
35
Vogelsberg-Ragaglia V, Schuck T, Trojanowski J Q, Lee V M. PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus. Exp Neurol , 2001, 168(2): 402-412
36
Sontag E, Luangpirom S, Hladik C, Mudrak I, Ogris S, Speciale S, White C L 3rd. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol , 2004, 63(4): 287-301
37
Liu R, Zhou X W, Tanila H, Bjorkdahl C, Wang J Z, Guan Z Z, Cao Y, Gustafsson J A, Winblad B, Pei J J. Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med , 2008, 12(1): 241-257
38
Sontag E, Nunbhakdi-Craig V, Lee G, Bloom G S, Mumby M C. Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron , 1996, 17(6): 1201-1207
39
Li M, Guo H, Damuni Z. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney. Biochemistry , 1995, 34(6): 1988-1996
40
Chen S, Li B, Grundke-Iqbal I, Iqbal K. I1PP2A affects tau phosphorylation via association with the catalytic subunit of protein phosphatase 2A. J Biol Chem , 2008, 283(16): 10513-10521
41
Tanimukai H, Grundke-Iqbal I, Iqbal K. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. Am J Pathol , 2005, 166(6): 1761-1771
42
Chung H, Nairn A C, Murata K, Brautigan D L. Mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the alpha 4 subunit which promotes dephosphorylation of elongation factor-2. Biochemistry , 1999, 38(32): 10371-10376
43
Kremmer E, Ohst K, Kiefer J, Brewis N, Walter G. Separation of PP2A core enzyme and holoenzyme with monoclonal antibodies against the regulatory A subunit: abundant expression of both forms in cells. Mol Cell Biol ,1997, 17(3): 1692-1701
44
SontagE. Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell Signal , 2001, 13(1): 7-16
45
Sontag E, Hladik C, Montgomery L, Luangpirom A, Mudrak I, Ogris E, White C L 3rd. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol , 2004, 63(10): 1080-1091
46
Gentry M S, Li Y, Wei H, Syed F F, Patel S H, Hallberg R L, Pallas D C. A novel assay for protein phosphatase 2A (PP2A) complexes in vivo reveals differential effects of covalent modifications on different Saccharomyces cerevisiae PP2A heterotrimers. Eukaryot Cell , 2005, 4(6): 1029-1040
47
Zhou X W, Gustafsson J A, Tanila H, Bjorkdahl C, Liu R, Winblad B, Pei J J. Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis , 2008, 31(3): 386-394
48
Sontag E, Nunbhakdi-Craig V, Sontag J M, Diaz-Arrastia R, Ogris E, Dayal S, Lentz S R, Arning E, Bottiglieri T. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci , 2007, 27(11): 2751-2759
49
Guo H, Reddy S A, Damuni Z. Purification and characterization of an autophosphorylation-activated protein serine threonine kinase that phosphorylates and inactivates protein phosphatase 2A. J Biol Chem , 1993, 268(15): 11193-11198
50
Brautigan D L. Flicking the switches: phosphorylation of serine/threonine protein phosphatases. Semin Cancer Biol , 1995, 6(4): 211-217
51
Chen J, Martin B L, Brautigan D L. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science , 1992, 257(5074): 1261-1264
52
Sontag E, Hladik C, Montgomery L, Luangpirom A, Mudrak I, Ogris E, White C L 3rd. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol , 2004, 63(10): 1080-1091