Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

Abstract

Mutations in the human tau gene cause frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17). One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Here we show that modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10. The effect is mediated by the formation of a stable pre-mRNA-oligonucleotide hybrid, which blocks access of the splicing machinery to the pre-mRNA. Correction of tau splicing occurs in a tau minigene system and in endogenous tau RNA in neuronal pheochromocytoma cells and is specific to exon 10 of the tau gene. Antisense oligonucleotide-mediated exclusion of exon 10 has a physiological effect by increasing the ratio of protein lacking the microtubule-binding domain encoded by exon 10. As a consequence, the microtubule cytoskeleton becomes destabilized and cell morphology is altered. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17. Mutations in the human tau gene cause frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17). One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Here we show that modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10. The effect is mediated by the formation of a stable pre-mRNA-oligonucleotide hybrid, which blocks access of the splicing machinery to the pre-mRNA. Correction of tau splicing occurs in a tau minigene system and in endogenous tau RNA in neuronal pheochromocytoma cells and is specific to exon 10 of the tau gene. Antisense oligonucleotide-mediated exclusion of exon 10 has a physiological effect by increasing the ratio of protein lacking the microtubule-binding domain encoded by exon 10. As a consequence, the microtubule cytoskeleton becomes destabilized and cell morphology is altered. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17. frontotemporal dementia and Parkinsonism associated with chromosome 17 polymerase chain reaction reverse transcriptase base pair(s) 1,4-piperazinediethanesulfonic acid phosphate-buffered saline rat E10β Alternative splicing is a major regulatory mechanism in gene expression. An estimated 40% of human genes are alternatively spliced, and about 15% of the reported mutations in human genetic diseases affect pre-mRNA splicing (1Hanke J. Brett D. Zastrow I. Aydin A. Delbruck S. Lehmann G. Luft F. Reich J. Bork P. Trends Genet. 1999; 15: 389-390Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 2Philips A.V. Cooper T.A. Cell. Mol. Life Sci. 2000; 57: 235-249Crossref PubMed Scopus (108) Google Scholar, 3Cooper T.A. Mattox W. Am. J. Hum. Genet. 1997; 61: 259-266Abstract Full Text PDF PubMed Scopus (231) Google Scholar). One of the diseases directly caused by mutations that result in pre-mRNA splicing defects is frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17)1 (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 5Foster N.L. Wilhelmsen K. Sima A.A. Jones M.Z. D'Amato C.J. Gilman S. Ann. Neurol. 1997; 41: 706-715Crossref PubMed Scopus (602) Google Scholar, 6Goedert M. Spillantini M.G. Davies S.W. Curr. Opin. Neurobiol. 1998; 8: 619-632Crossref PubMed Scopus (227) Google Scholar). FTDP-17 is an autosomal-dominant disorder related to Alzheimer's disease. Symptoms of FTDP-17 include personality changes, reduced speech, and dementia. In late stages, memory loss occurs, and the disease becomes virtually indistinguishable from Alzheimer's disease (7Wilhelmsen K.C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7120-7121Crossref PubMed Scopus (22) Google Scholar). The disease gene for FTDP-17 has been identified by positional cloning as the tau gene, which encodes a microtubule-binding protein (8Hong M. Zhukareva V. Wszolek Z. Reed L. Miller B.I. Geschwind D.H. Bird T.D. McKeel D. Goate A. Morris J.C. Wilhelmsen K.C. Schellenberg G.D. Tojanowski J.Q. Lee V.M.-Y. Science. 1998; 282: 1914-1917Crossref PubMed Scopus (821) Google Scholar, 9Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. Pickering-Brown S. Chakraverty S. Nature. 1998; 393: 702-705Crossref PubMed Scopus (2915) Google Scholar). In FTDP-17, tau is incorporated into aggregates of fibrillar tangles and paired helical filaments, leading to neuronal cell death causing the neurological symptoms of the disease (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 6Goedert M. Spillantini M.G. Davies S.W. Curr. Opin. Neurobiol. 1998; 8: 619-632Crossref PubMed Scopus (227) Google Scholar, 10Clark L.N. Poorkaj P. Wszolek Z. Geschwind D.H. Nasreddine Z.S. Miller B. Li D. Payami H. Awert F. Markopoulou K. Andreadis A. D'Souza I. Lee V.M. Reed L. Trojanowski J.Q. Zhurakeva V. Bird T. Schellenberg G. Wilhelmsen K.C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13103-13107Crossref PubMed Scopus (449) Google Scholar, 11Barghorn S. Zheng-FIschhofer Q. Ackmann M. Biernat J. von Bergen M. Mandelkow E.M. Mandelkow E. Biochemistry. 2000; 39: 11714-11721Crossref PubMed Scopus (293) Google Scholar). Apart from FTDP-17, tau deposits are also the defining pathological feature of several neurological disorders including Alzheimer's disease, progressive supranuclear palsy, and Niemann-Pick disease (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 6Goedert M. Spillantini M.G. Davies S.W. Curr. Opin. Neurobiol. 1998; 8: 619-632Crossref PubMed Scopus (227) Google Scholar). Tau is a microtubule-binding protein that normally promotes microtubule assembly and stability (12Kanai Y. Chen J. Hirokawa N. EMBO J. 1992; 11: 3953-3961Crossref PubMed Scopus (153) Google Scholar, 13Goode B.L. Chau M. Denis P.E. Feinstein S.C. J. Biol. Chem. 2000; 275: 38182-38189Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 14Buee L. Bussiere T. Buee-Scherrer V. Delacourte A. Hof P.R. Brain Res. 2000; 33: 95-130Crossref Scopus (1559) Google Scholar, 15Friedhoff P. von Bergen M. Mandelkow E.M. Mandelkow E. Biochim. Biophys. Acta. 2000; 1501: 122-132Crossref Scopus (135) Google Scholar). The microtubule-binding domains are encoded by exons 9–12 (16Lee G. Neve R.L. Kosik K.S. Neuron. 1989; 2: 1615-1624Abstract Full Text PDF PubMed Scopus (365) Google Scholar). In human brain, six tau isoforms are expressed as the result of alternative use of exon 2, exon 3, and exon 10, which encodes one of the microtubule-binding domains (17Goedert M. Spillantini M.G. Jakes R. Rutherford D. Crowther R.A. Neuron. 1989; 3: 519-526Abstract Full Text PDF PubMed Scopus (1858) Google Scholar). Increased inclusion of exon 10 results in an elevated level of tau protein containing an additional fourth microtubule-binding domain (the 4R isoform) relative to tau protein containing only three microtubule-binding domains (the 3R isoform). Increased inclusion of tau exon 10 is tightly correlated with the disease phenotype, and overproduction of 4R tau is sufficient for disease (10Clark L.N. Poorkaj P. Wszolek Z. Geschwind D.H. Nasreddine Z.S. Miller B. Li D. Payami H. Awert F. Markopoulou K. Andreadis A. D'Souza I. Lee V.M. Reed L. Trojanowski J.Q. Zhurakeva V. Bird T. Schellenberg G. Wilhelmsen K.C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13103-13107Crossref PubMed Scopus (449) Google Scholar, 18Goedert M. Crowther R.A. Spillantini M.G. Neuron. 1998; 21: 955-958Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar). The increase in exon 10 inclusion is due to mutations at the 3′-end of exon 10, which result in the destabilization of an RNA stem-loop (19Varani L. Hasegawa M. Spillantini M.G. Smith M.J. Murrel J.R. Ghetti B. Klug A. Goedert M. Varani G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8229-8234Crossref PubMed Scopus (200) Google Scholar). In healthy individuals, this loop prevents access of the splicing machinery to exon 10, thus blocking its inclusion into the mRNA. When mutated, the stem-loop is destabilized, and the splice junction in exon 10 can be used (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 19Varani L. Hasegawa M. Spillantini M.G. Smith M.J. Murrel J.R. Ghetti B. Klug A. Goedert M. Varani G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8229-8234Crossref PubMed Scopus (200) Google Scholar, 20Hasegawa M. Smith M.J. Iijima M. Tabira T. Goedert M. FEBS Lett. 1999; 443: 93-96Crossref PubMed Scopus (174) Google Scholar, 21Grover A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 22D'Souza I. Poorkaj P. Hong M. Nochlin D. Lee V.M. Bird T.D. Schellenberg G.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5598-5603Crossref PubMed Scopus (421) Google Scholar, 23Gao Q.-S. Memmott J. Lafyatis R. Stamm S. Screaton G. Andreadis A. J. Neurochem. 2000; 74: 490-500Crossref PubMed Scopus (78) Google Scholar). In addition, cis-acting elements within exon 10 also contribute to splice site choice (23Gao Q.-S. Memmott J. Lafyatis R. Stamm S. Screaton G. Andreadis A. J. Neurochem. 2000; 74: 490-500Crossref PubMed Scopus (78) Google Scholar, 24D'Souza I. Schellenberg G.D. J. Biol. Chem. 2000; 275: 17700-17709Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Here we report the application of antisense oligonucleotides to reverse the inclusion of tau exon 10 into mRNA as observed in FTDP-17 patients. Modified antisense oligonucleotides directed against either splice junction of exon 10 efficiently corrected its inclusion into tau mRNA. The oligonucleotides elicited a physiological effect by reducing the level of tau protein containing the microtubule-binding domain encoded by exon 10, and as a consequence the cytoskeleton morphology was altered. The use of antisense oligonucleotides will be useful to study the physiological role of specific tau isoforms in disease and cellular differentiation, and it might provide a novel therapeutic strategy to treat FTDP-17 and other tauopathies. COS-1 green monkey kidney cells (ATCC entry CRL-1650) in modified at cells (ATCC entry in other at a ratio of about was used to cell cells (ATCC entry in oligonucleotides a and by results with oligonucleotides from either from rat to the cells a of the tau minigene and oligonucleotides into COS-1 was used to the a ratio of of in of modified used of of was in of as by of oligonucleotides. a was by cells in of modified and several a of cell in at was in a a was to with in about of with and RNA was the to the from in of and for at at in of and RNA in and a RNA was with of for and was at for Life reverse transcriptase and used for reverse The reverse reaction was to of RNA in in a The reaction was for at to and of Life and of reverse transcriptase to a of The reaction was for at transcriptase was at for 10 the of the of and of was at of at at at 10 at a for of tau in the splice and of of the The and and the of and of endogenous tau from cells and in exon and as by A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google The of the was and as 10 at of at at at 10 at of splicing of exons and and as 10 at of at at and at 10 at The of the was for the including exons and 3, for the including exon and for the exon The for was in with and tau in the of and with endogenous tau from cells in the of and by The for tau and for rat within the containing a system and with as by M. M. V. T. Brain Res. 2000; Scholar). cells and the was was for at of protein an and with a and at with in by in for at The was the and a system cells and as for COS-1 cells for in in in and for with in three for in and for with in three for and in was a a was at and was and of a with a and are to inclusion of exon 10 into tau mRNA by use of antisense oligonucleotides. Our was to into cells containing to the splice site of exon 10 a and In to antisense oligonucleotides RNA stable B. U. J. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar). Our was that the oligonucleotides access of the splicing machinery to the splice junction and in this the inclusion of the tau exon 10 into the mRNA a and antisense oligonucleotides to tau exon 10 of the splicing of tau exon 10, we used a minigene system that to a the of exon 10 in the of the tau gene A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). The splicing of exon 10 in the minigene was by RNA of the minigene into COS-1 cells As of the exon 10 minigene in COS-1 cells in exclusion of exon 10 A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). The of the tau was In to the in FTDP-17 of exon 10 containing a at in inclusion of exon 10 The of the tau was increased to results with at and 21Grover A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). The of the was by antisense oligonucleotides reverse the inclusion of the exon 10, COS-1 cells with exon 10 minigene containing the and increasing of antisense to the splice junction of exon 10, oligonucleotides inclusion of exon 10 efficiently and effect was at for either observed of the was observed in and was in the A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). The exclusion of exon 10 was oligonucleotides containing the in effect exon 10 inclusion at to and The that the RNA in cells with and cells with of to that the oligonucleotides an RNA mechanism E10β a to tau at this reduced the of the we E10β tau containing in to the is also the of E10β a tau minigene with a in which is of the E10β A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). E10β was in the inclusion of exon 10 into either one of tau that a in E10β to tau affect its that this effect was specific to the tau minigene and was due to in the splicing in COS-1 cells caused by the of the the effect of and E10β the alternative splicing of a minigene containing the was a splice site which to 10, and Stamm S. Science. PubMed Scopus Google Scholar, M. G. J. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). When COS-1 cells with and either one of the antisense effect splicing 2, and effect a minigene containing the alternatively exon P. A. S. J. PubMed Scopus Google the results demonstrate that antisense oligonucleotides to tau exon 10 splice junctions inclusion of exon 10 during the splicing that this occurs in a and that the effect tau exon 10 splicing is to antisense oligonucleotides can also exclusion of tau exon 10 in the of the endogenous this we used rat neuronal pheochromocytoma cells the and thus useful to modified oligonucleotides the to the C.J. FEBS Lett. PubMed Scopus Google The inclusion of exon 10 in rat tau is due to three the splice which mutations in human tau A. Houlden H. Baker M. Adamson J. Lewis J. Prihar G. Pickering-Brown S. Duff K. Hutton M. J. Biol. Chem. 1999; 274: 15134-15143Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). cells with increasing of rat is to that it three to it to the rat The alternative splicing of rat tau mRNA was by in exons and As in the minigene antisense oligonucleotides exon 10 from the tau mRNA 3, and effect was at for and rat with the minigene the due to of cells with oligonucleotides antisense oligonucleotides of the base as rat in effect tau splicing at to 10 3, and E10β against the human tau gene a the effect of the antisense oligonucleotides was specific to tau exon 10, we the splicing of the alternatively exons and in tau in exons and rat E10β effect the splicing of exons and in endogenous tau effect alternative splicing of the gene, an protein P. A. E. D. M. M. S. P. P. J. 2000; PubMed Scopus Google These results show that inclusion of tau exon 10 in the of its endogenous pre-mRNA is by the of antisense that this occurs in an and that the effect tau exon 10 splicing is specific and has effect other alternative splicing in the gene. the effect of antisense oligonucleotides was to the RNA was into a in the relative of 3R and 4R protein we cells with either a of either rat for and tau several and as M. M. V. T. Brain Res. 2000; Scholar). six tau protein isoforms the As three of in cells In the the 4R and the the 3R (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, M. M. V. T. Brain Res. 2000; Scholar). The three to the isoforms containing exons and exon exon exon is (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). In cells with the 4R was in In of cells with rat E10β in the increased of the 3R in as by the of the of that the relative in 4R from about for the to about for the These results that with antisense oligonucleotides increased the relative of 3R protein in Tau is a and the 3R and the 4R been the for is S. Zheng-FIschhofer Q. Ackmann M. Biernat J. von Bergen M. Mandelkow E.M. Mandelkow E. Biochemistry. 2000; 39: 11714-11721Crossref PubMed Scopus (293) Google Scholar, M. Jakes R. EMBO J. PubMed Scopus Google Scholar, B.L. Feinstein S.C. J. Biol. PubMed Scopus Google Scholar). to the the 3R and the 4R the ratio the isoforms might affect to microtubule morphology in cells due to and As an we the morphology in rat which been to 4R tau isoforms P. L. J. Sci. 1998; Google Scholar). cells either with a of either rat and the cells for As in cells cells with the the tau was expressed In either one of the oligonucleotides to the splice junction exon 10 exclusion and to the formation of the tau cells with in and indistinguishable from that the of has effect cell morphology The cells and in cells leading be observed In cells with either rat E10β in to the directly the microtubule cells with an In cells and in cells with a microtubule was of several in the and at the of cells that the are of the cell and thus show the and the In in cells with oligonucleotides rat microtubule observed and was to the of the and be of the cell with this These results show that a in 4R tau protein has a physiological effect by the microtubule cytoskeleton and cell show that modified antisense oligonucleotides to the and of exon 10 of tau pre-mRNA inclusion of this exon into the mRNA during the splicing The effect is to the protein and a physiological effect by a in the microtubule The of was to access of the splicing machinery to either splice thus inclusion of the strategy the of exon 10 splicing in In human brain, inclusion of exon 10 is by a stem-loop at the 3′-end of exon 10 by the of exon 10 and in the (4Spillantini M.G. 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The stem-loop an site for the RNA and thus the splicing of exon 10 of splicing by the stem-loop is for the disease mutations in the 3′-end of human tau exon 10 and the contribute in to exon 10 mutations the in increased access of the splicing machinery to the splice reported mutations also increase the of the splice site to the of the The antisense oligonucleotides the of the stem-loop by the access of to the 3′-end of exon 10. of splice to be an to splice site choice in Antisense oligonucleotides been used in several other including and to access of the splicing machinery to an splice site H. M.J. S. R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, G. H. S. J. D. R. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, M.G. M. P. G. Hum. Mol. Genet. 1998; PubMed Scopus Google Scholar, C.J. K. T. F. S. T.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, F. K. S. K. S. R. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. R. J. 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PubMed Scopus Google Scholar). it is that the of an additional microtubule-binding domain in the 4R isoforms an effect to the three microtubule-binding domains a protein with B.L. Chau M. Denis P.E. Feinstein S.C. J. Biol. Chem. 2000; 275: 38182-38189Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). that the use of antisense oligonucleotides will be a useful tool for the study of vivo of tau of the relative of tau isoforms antisense oligonucleotides will be useful to the role of tau in cell and in the disease and also for therapeutic in FTDP-17. of the tau gene in increased inclusion of exon 10 is as a cause for FTDP-17, FTDP-17 mutations result in splicing defects (4Spillantini M.G. Goedert M. Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, M. Zhukareva V. Wszolek Z. Reed L. Miller B.I. Geschwind D.H. Bird T.D. McKeel D. Goate A. Morris J.C. Wilhelmsen K.C. Schellenberg G.D. Tojanowski J.Q. Lee V.M.-Y. 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