Effect of Pin1 or Microtubule Binding on Dephosphorylation of FTDP-17 Mutant Tau

Abstract

Neurodegenerative tauopathies, including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein Tau. One group of tauopathies, known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), is directly associated with mutations of the gene tau. However, it is unknown why mutant Tau is highly phosphorylated in the patient brain. In contrast to in vivo high phosphorylation, FTDP-17 Tau is phosphorylated less than wild-type Tau in vitro. Because phosphorylation is a balance between kinase and phosphatase activities, we investigated dephosphorylation of mutant Tau proteins, P301L and R406W. Tau phosphorylated by Cdk5-p25 was dephosphorylated by protein phosphatases in rat brain extracts. Compared with wild-type Tau, R406W was dephosphorylated faster and P301L slower. The two-dimensional phosphopeptide map analysis suggested that faster dephosphorylation of R406W was due to a lack of phosphorylation at Ser-404, which is relatively resistant to dephosphorylation. We studied the effect of the peptidyl-prolyl isomerase Pin1 or microtubule binding on dephosphorylation of wild-type Tau, P301L, and R406W in vitro. Pin1 catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro sequences in a subset of proteins. Dephosphorylation of wild-type Tau was reduced in brain extracts of Pin1-knockout mice, and this reduction was not observed with P301L and R406W. On the other hand, binding to microtubules almost abolished dephosphorylation of wild-type and mutant Tau proteins. These results demonstrate that mutation of Tau and its association with microtubules may change the conformation of Tau, thereby suppressing dephosphorylation and potentially contributing to the etiology of tauopathies. Neurodegenerative tauopathies, including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein Tau. One group of tauopathies, known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), is directly associated with mutations of the gene tau. However, it is unknown why mutant Tau is highly phosphorylated in the patient brain. In contrast to in vivo high phosphorylation, FTDP-17 Tau is phosphorylated less than wild-type Tau in vitro. Because phosphorylation is a balance between kinase and phosphatase activities, we investigated dephosphorylation of mutant Tau proteins, P301L and R406W. Tau phosphorylated by Cdk5-p25 was dephosphorylated by protein phosphatases in rat brain extracts. Compared with wild-type Tau, R406W was dephosphorylated faster and P301L slower. The two-dimensional phosphopeptide map analysis suggested that faster dephosphorylation of R406W was due to a lack of phosphorylation at Ser-404, which is relatively resistant to dephosphorylation. We studied the effect of the peptidyl-prolyl isomerase Pin1 or microtubule binding on dephosphorylation of wild-type Tau, P301L, and R406W in vitro. Pin1 catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro sequences in a subset of proteins. Dephosphorylation of wild-type Tau was reduced in brain extracts of Pin1-knockout mice, and this reduction was not observed with P301L and R406W. On the other hand, binding to microtubules almost abolished dephosphorylation of wild-type and mutant Tau proteins. These results demonstrate that mutation of Tau and its association with microtubules may change the conformation of Tau, thereby suppressing dephosphorylation and potentially contributing to the etiology of tauopathies. One of hallmarks of Alzheimer disease (AD) 3The abbreviations used are: ADAlzheimer diseaseCdk5cyclin-dependent kinase 5FTDP-17frontotemporal dementia with parkinsonism linked to chromosome 17GSK3βglycogen synthase kinase 3βMTmicrotubulePHFpaired helical filamentPKAcAMP-dependent protein kinasePP1protein phosphatase 1PP2Aprotein phosphatase 2AMOPS4-morpholinepropanesulfonic acidWTwild type. 3The abbreviations used are: ADAlzheimer diseaseCdk5cyclin-dependent kinase 5FTDP-17frontotemporal dementia with parkinsonism linked to chromosome 17GSK3βglycogen synthase kinase 3βMTmicrotubulePHFpaired helical filamentPKAcAMP-dependent protein kinasePP1protein phosphatase 1PP2Aprotein phosphatase 2AMOPS4-morpholinepropanesulfonic acidWTwild type. pathology is neurofibrillary tangles, which are composed of paired helical filaments (PHFs), aggregates of the abnormally phosphorylated microtubule-associated protein Tau. Intracellular inclusions comprising Tau are also found in several other neurodegenerative diseases, including Pick disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), collectively called tauopathies (1Lee V.M. Goedert M. Trojanowski J.Q. Annu. Rev. Neurosci. 2001; 24: 1121-1159Crossref PubMed Scopus (2110) Google Scholar, 2Goedert M. Spillantini M.G. Science. 2006; 314: 777-781Crossref PubMed Scopus (1573) Google Scholar, 3Hasegawa M. Neuropathology. 2006; 26: 484-490Crossref PubMed Scopus (46) Google Scholar). Identification of Tau as a causative gene of the inherited tauopathy FTDP-17 reveals that Tau mutation is sufficient to cause disease (4Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. Pickering-Brown S. Chakraverty S. Isaacs A. Grover A. Hackett J. Adamson J. Lincoln S. Dickson D. Davies P. Petersen R.C. Stevens M. de Graaff E. Wauters E. van Baren J. Hillebrand M. Joosse M. Kwon J.M. Nowotny P. Che L.K. Norton J. Morris J.C. Reed L.A. Trojanowski J. Basun H. Lannfelt L. Neystat M. Fahn S. Dark F. Tannenberg T. Dodd P.R. Hayward N. Kwok J.B. Schofield P.R. Andreadis A. Snowden J. Craufurd D. Neary D. Owen F. Oostra B.A. Hardy J. Goate A. van Swieten J. Mann D. Lynch T. Heutink P. Nature. 1998; 393: 702-705Crossref PubMed Scopus (2889) Google Scholar, 5Poorkaj P. Bird T.D. Wijsman E. Nemens E. Garruto R.M. Anderson L. Andreadis A. Wiederholt W.C. Raskind M. Schellenberg G.D. Ann. Neurol. 1998; 43: 815-825Crossref PubMed Scopus (1219) Google Scholar, 6Spillantini M.G. Crowther R.A. Jakes R. Hasegawa M. Goedert M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6469-6473Crossref PubMed Scopus (2364) Google Scholar). However, the impact Tau mutations have on neurodegeneration remains unknown. Alzheimer disease cyclin-dependent kinase 5 frontotemporal dementia with parkinsonism linked to chromosome 17 glycogen synthase kinase 3β microtubule paired helical filament cAMP-dependent protein kinase protein phosphatase 1 protein phosphatase 2A 4-morpholinepropanesulfonic acid wild type. Alzheimer disease cyclin-dependent kinase 5 frontotemporal dementia with parkinsonism linked to chromosome 17 glycogen synthase kinase 3β microtubule paired helical filament cAMP-dependent protein kinase protein phosphatase 1 protein phosphatase 2A 4-morpholinepropanesulfonic acid wild type. Tau proteins in inclusions are hyperphosphorylated, and extensive studies have identified the phosphorylation sites; for example, more than 20 sites have been identified in PHF-Tau obtained from AD brains (7Morishima-Kawashima M. Hasegawa M. Takio K. Suzuki M. Yoshida H. Titani K. Ihara Y. J. Biol. Chem. 1995; 270: 823-829Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar, 8Hanger D.P. 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Full Text Full Text PDF PubMed Scopus Google thereby a more However, its effect on dephosphorylation of mutant Tau not been We dephosphorylation of Tau and in brain extracts from and of was as the for the Dephosphorylation of was in brain with brain and and the dephosphorylation of Pin1 at a that is sufficient to the dephosphorylation in J. H. Uchida C. Uchida T. 2006; PubMed Scopus Google Scholar). is with the that Pin1 dephosphorylation of by C. J.M. A. L. G. 43: PubMed Scopus Google Scholar). We dephosphorylation of and in and extracts. was less of a in dephosphorylation between and brain in P301L and R406W with of Pin1 to brain not the dephosphorylation of and These results that FTDP-17 mutations of to of dephosphorylation. We the effect of Pin1 on dephosphorylation was for the phospho-Ser/Thr-Pro this in to we used other protein kinases, a kinase, and a kinase, to Tau. of was Tau with protein two-dimensional phosphopeptide between as on phosphorylation sites phosphopeptide are to of and Tau A. Biernat J. M. Mandelkow E. Mandelkow E.M. Scopus Google Scholar). Tau phosphorylated by or was dephosphorylated by brain The dephosphorylation of Tau as as Tau was in the of brain this was not the for Tau, with results that the effect of Pin1 on dephosphorylation is for phosphorylation sequences A. M. G. G. M. G. Full Text Full Text PDF PubMed Scopus Google Scholar, C. J.M. A. L. G. 43: PubMed Scopus Google Scholar, P. S. K. D. M. L. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of Tau is Tau is on microtubules Y. K. Uchida T. H. T. T. S. J. Biochem. 1998; PubMed Scopus Google Scholar). phosphorylation by or Cdk5-p25 of mutant Tau to microtubules is to the as that of Tau F. T. Y. A. 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Chem. 71: PubMed Scopus Google and we that Tau not of microtubules in We Tau to microtubules and dephosphorylation. the of Tau not its dephosphorylation The results suggested binding to its conformation that dephosphorylation is demonstrate this more we used a mutant Tau, in which the to the Tau was not to microtubules as G. G. N. M. J. Neurosci. PubMed Scopus Google it was phosphorylated at the sites as Tau, as by two-dimensional phosphopeptide Tau and Tau dephosphorylated at with brain dephosphorylation of was not in the of results that the binding of to microtubules its dephosphorylation. We the effect of Pin1 on dephosphorylation of Tau to of Pin1 to brain not the dephosphorylation of Tau to microtubules with in in the of microtubules is in of results obtained with P301L and R406W Pin1 to the dephosphorylation of the was not Pin1 not the of dephosphorylation microtubule We investigated dephosphorylation of P301L, and phosphorylated by Compared with Tau, was dephosphorylated faster and slower. The dephosphorylation between phosphorylation sites; was dephosphorylated and was faster than The why which phosphorylation, was dephosphorylated faster than Tau or We that dephosphorylation of Tau was in brain is that the Pin1 was by the FTDP-17 mutation of Tau. dephosphorylation of or was almost abolished binding to These demonstrate that the phosphorylation of Tau are not by of protein also by dephosphorylation that on the of Tau or is a of Tau in brains K. Alonso Adel C. Chen S. Chohan M.O. El-Akkad E. Gong C.X. S. B. F. A. H. PubMed Scopus Google Scholar, J. 2006; PubMed Scopus Google Scholar, T. M. R. Heutink P. van Swieten J.C. K. Ihara Y. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). However, it is not known FTDP-17 mutations was a between in vivo and in phosphorylation of FTDP-17 Tau N. T. Ihara Y. J. Full Text Full Text PDF PubMed Scopus Google Scholar, R. M. L. K. Anderton B.H. M. S. PubMed Scopus Google Scholar, M. F. M. J. J. Neurochem. PubMed Scopus Google Scholar, N. T. H. J. Neurosci. PubMed Scopus Google Scholar, T. M. R. Heutink P. van Swieten J.C. K. Ihara Y. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation of mutant Tau A. C. A. M. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the that abnormal phosphorylation of mutant Tau remains to be Because phosphorylation is a balance between kinase and phosphatase activities, we this with to which for FTDP-17 mutant not been We P301L and R406W of FTDP-17 mutation that have been The P301L, is of the identified mutations in FTDP-17 and M.G. Crowther R.A. Jakes R. Hasegawa M. Goedert M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6469-6473Crossref PubMed Scopus (2364) Google Scholar, T.D. D. P. M. J. H. E. Nemens E. Schellenberg G.D. PubMed Scopus Google Scholar, Swieten J.C. Stevens M. Rizzu P. Joosse M. de R. Spillantini M.G. Heutink P. Ann. Neurol. PubMed Scopus Google Scholar). R406W is and (4Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. Pickering-Brown S. Chakraverty S. Isaacs A. Grover A. Hackett J. Adamson J. Lincoln S. Dickson D. Davies P. Petersen R.C. Stevens M. de Graaff E. Wauters E. van Baren J. Hillebrand M. Joosse M. Kwon J.M. Nowotny P. Che L.K. Norton J. Morris J.C. Reed L.A. Trojanowski J. Basun H. Lannfelt L. Neystat M. Fahn S. Dark F. Tannenberg T. Dodd P.R. Hayward N. Kwok J.B. Schofield P.R. Andreadis A. Snowden J. Craufurd D. Neary D. Owen F. Oostra B.A. Hardy J. Goate A. van Swieten J. Mann D. Lynch T. Heutink P. Nature. 1998; 393: 702-705Crossref PubMed Scopus (2889) Google Scholar, L.A. Morris J.C. Goate A. A. Trojanowski J.Q. Ann. Neurol. 1997; PubMed Scopus Google Scholar). These mutations in P301L can filaments on its T. M. R. Heutink P. van Swieten J.C. K. Ihara Y. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Joosse M. R. A. van Swieten J.C. R. Heutink P. PubMed Scopus Google R406W filaments by with Tau T. M. R. Heutink P. van Swieten J.C. K. Ihara Y. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Hasegawa M. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In studies have that P301L and R406W mutations the of Tau to microtubule M. Goedert M. 1998; PubMed Scopus Google Scholar, M. Reed L. Bird T.D. D. Goate A. Morris J.C. Schellenberg G.D. Trojanowski J.Q. V.M. Science. 1998; PubMed Scopus Google the effect of R406W on microtubules is to that of Tau in J.M. K. L. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). a in dephosphorylation was also found between P301L and R406W. P301L was dephosphorylated than Tau, and R406W was dephosphorylated faster than Tau. the effect of FTDP-17 mutations on dephosphorylation was as a of protein phosphatases D. PubMed Scopus Google Scholar). that FTDP-17 have to P301L than reduced dephosphorylation of P301L may at in for the observed high of phosphorylation of mutant Tau in brains with tauopathies. P301L and R406W are highly phosphorylated in of dephosphorylation in vitro. in phosphorylation phosphorylated and in P301L as as Tau. was dephosphorylated faster and was dephosphorylated by protein phosphatases in brain The of to dephosphorylation was M. van L. H. M. M. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). P301L, R406W is not phosphorylated on The lack of phosphorylation in the R406W mutant also been in brain M. F. M. J. J. Neurochem. PubMed Scopus Google Scholar, Betts J.C. Blackstock W.P. J. S. M. Anderton B.H. Scopus Google Scholar, Y. T. T. K. K. M. K. M. K. E. S. T. A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of in the to may of the phosphorylation the of phosphorylation at a that is dephosphorylated in other results in the faster dephosphorylation of R406W. However, the phosphorylation in the and is at phosphorylation at and in a Y. E. S. T. N. M. N. K. R. A. J. 2006; PubMed Scopus Google Scholar). In it also been that phosphorylation is in R406W phosphorylated in by brain in the of acid A. C. A. M. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). may be to the phosphorylation and dephosphorylation of and in phosphorylation at and is known as the of the abnormal phosphorylation sites in Tau L. L. E. Goedert M. V.M. J. Neurosci. PubMed Scopus Google Scholar). The in dephosphorylation not the observed high phosphorylation of mutant P301L the phosphorylation as Tau. We not the to the at the of in Tau may be in this The P301L mutation is in the of the that is found in Tau. mutation is to change the conformation to the of the from to D. M. A. Biernat J. C. Mandelkow E. M. PubMed Scopus (46) Google Scholar). change may the of in the which are the with phosphorylation sites in the may in reduced by protein We Pin1 between mutant and Pin1 the dephosphorylation of the phospho-Ser/Thr-Pro by A. M. G. G. M. G. Full Text Full Text PDF PubMed Scopus Google Scholar). Pin1 is in AD the protein is in neurofibrillary tangles, and Tau is in brains G. Davies P. Nature. PubMed Scopus Google Scholar). We that Pin1 dephosphorylation of by and this dephosphorylation at phosphorylation was of the of dephosphorylation in P301L and R406W. These results that P301L and R406W be phosphorylated more in Pin1 brain. We why the dephosphorylation of FTDP-17 was to and may have a conformation that be by Pin1 binding sites in Tau are to be G. Davies P. Nature. PubMed Scopus Google or C. J.M. A. L. G. 43: PubMed Scopus Google Scholar, R. J.M. H. P. L. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation sites at and Ser-404, are not in Pin1 binding may be Pin1 binding sites phosphorylation was that Pin1 the in vivo of P301L and P301L is by Pin1 R406W and Tau are J. M. K. A. G. L. V.M. J. PubMed Scopus Google Scholar). be to between dephosphorylation of and to microtubules dephosphorylation of Tau. In results with of E. G. R. C. J. C.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that dephosphorylation of Tau by is reduced in the of of from We to that E. G. R. C. J. C.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Tau, which was to by with the and dephosphorylated of microtubules with that microtubules as a that not to In dephosphorylation of or of which not as as Tau in the of that Tau resistant to dephosphorylation by binding to The may be from the protein phosphatase we used rat brain extracts that of including E. G. R. C. J. C.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google used In that dephosphorylation of Tau is in the of microtubules of Tau is phosphorylated by or We that the is by a change in Tau microtubule which Tau been to lack a of Tau also been N. 2006; PubMed Scopus Google Scholar, S. M. H. Mandelkow E. 2006; PubMed Scopus Google Scholar). remains Tau conformation binding to binding in the the phosphorylation and phosphorylation M. Biernat J. D. C. Mandelkow E. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it is highly that of or phosphatases to phosphorylation sites is by microtubule dephosphorylation of Tau to microtubules may the of Tau, which is resistant to dephosphorylation by protein phosphatases H. Hasegawa M. T. K. Ihara Y. E. J. Biochem. 1995; PubMed Scopus Google Scholar). Tau a conformation to that of Tau on of of dephosphorylation may to the by which Tau remains results a for mutant Tau remains highly phosphorylated in the brains of FTDP-17 The phosphorylation of FTDP-17 is to P301L than R406W. high phosphorylation of may be by a reduced of dephosphorylation by Tau a to in to to of which to microtubules with affinity than other in J.M. K. L. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). the R406W mutant Tau may a to other which dephosphorylation to R406W on microtubules may with or with phosphorylated Tau. between phosphorylated Tau on microtubules may or aggregates that be relatively resistant to dephosphorylation. In the of Tau, association with microtubules also may as it been high phosphorylation of Tau its to from microtubules (9Mandelkow E.M. Biernat J. Drewes G. Gustke N. Trinczek B. Mandelkow E. Neurobiol. Aging. 1995; 16 (discussion 362–363): 355-362Crossref PubMed Scopus (245) Google Scholar, 11Iqbal K. Alonso Adel C. Chen S. Chohan M.O. El-Akkad E. Gong C.X. S. B. F. A. H. PubMed Scopus Google Scholar). Compared with mutant Tau proteins, Tau, from is dephosphorylated to the by and Tau is less to aggregates the with