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Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription

Nature Genetics volume 26, pages 29–36 (2000)Cite this article

Abstract

At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

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Figure 1: Interaction between TAFII130 and polyQ stretches was demonstrated by the yeast two-hybrid assay (a), the far western assay (b) and the co-precipitation assay (c).
Figure 2: TAFII130 co-localizes with aggregate bodies in transient expression systems.
Figure 3: Co-localization of TAFII130 with NIIs in the autopsied brains of DRPLA and MJD/SCA3 cases.
Figure 4: Co-localization of NIIs with the transcription factors CREB, Sp1 and TBP in the autopsied brains of DRPLA and MJD/SCA3 cases.
Figure 5: Expanded polyQ stretches inhibit CREB-dependent transcriptional activation.
Figure 6: TAFII130 restores CREB-dependent transcriptional activation inhibited by an expanded polyQ stretch (Q82).
Figure 7: Suppression of expanded polyQ stretch-induced cytotoxicity by TAFII130.

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References

  1. Ross, C.A. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19, 1147–1150 (1997).

    Article  CAS  Google Scholar 

  2. Zhuchenko, O. et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nature Genet. 15, 62–69 (1997).

    Article  CAS  Google Scholar 

  3. Ikeda, H. et al. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Genet. 13, 196–202 (1996).

    Article  CAS  Google Scholar 

  4. Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    Article  CAS  Google Scholar 

  5. Skinner, P.J. et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–974 (1997).

    Article  CAS  Google Scholar 

  6. Davies, S.W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    Article  CAS  Google Scholar 

  7. DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    Article  CAS  Google Scholar 

  8. Paulson, H.L. et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19, 333–344 (1997).

    Article  CAS  Google Scholar 

  9. Igarashi, S. et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nature Genet. 18, 111–117 (1998).

    Article  CAS  Google Scholar 

  10. Li, M. et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann. Neurol. 44, 249–254 (1998).

    Article  CAS  Google Scholar 

  11. Holmberg, M. et al. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet. 7, 913–918 (1998).

    Article  CAS  Google Scholar 

  12. Koyano, S. et al. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci. Lett. 273, 117–120 (1999).

    Article  CAS  Google Scholar 

  13. Simental, J.A., Sar, M., Lane, M.V., French, F.S. & Wilson, E.M. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J. Biol. Chem. 266, 510–518 (1991).

    CAS  PubMed  Google Scholar 

  14. Tait, D. et al. Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum. Mol. Genet. 7, 991–997 (1998).

    Article  CAS  Google Scholar 

  15. Miyashita, T. et al. Intracellular aggregate formation of dentatorubral-pallidoluysian atrophy (DRPLA) protein with the expanded polyglutamine. Biochem. Biophys. Res. Commun. 249, 96–102 (1998).

    Article  CAS  Google Scholar 

  16. Sato, A. et al. Adenovirus-mediated expression of mutant DRPLA proteins with expanded polyglutamine stretches in neuronally differentiated PC12 cells. Preferential intranuclear aggregate formation and apoptosis. Hum. Mol. Genet. 8, 997–1006 (1999).

    Article  CAS  Google Scholar 

  17. Kaytor, M.D. et al. Nuclear localization of spinocerebellar ataxia type 7 protein, ataxin-7. Hum. Mol. Genet. 8, 1657–1664 (1999).

    Article  CAS  Google Scholar 

  18. Goldberg, Y.P. et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442–449 (1996).

    Article  CAS  Google Scholar 

  19. Klement, I.A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41–53 (1998).

    Article  CAS  Google Scholar 

  20. Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    Article  CAS  Google Scholar 

  21. Tanese, N., Saluja, D., Vassallo, M.F., Chen, J.-L. & Admon, A. Molecular cloning and analysis of two subunits of the human TFIID complex: hTAFII130 and hTAFII100. Proc. Natl. Acad. Sci. USA 93, 13611–13616 (1996).

    Article  CAS  Google Scholar 

  22. Mengus, G., May, M., Carré, L., Chambon, P. & Davidson, I. Human TAFII135 potentiates transcriptional activation by the AF-2s of the retinoic acid, vitamin D3, and thyroid hormone receptors in mammalian cells. Genes Dev. 11, 1381–1395 (1997).

    Article  CAS  Google Scholar 

  23. Schilling, G. et al. Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24, 275–286 (1999).

    Article  CAS  Google Scholar 

  24. Newmeyer, D.D. & Forbes, D.J. Nuclear import can be separated into distinct steps in vitro: nuclear pore binding and translocation. Cell 52, 641–653 (1988).

    Article  CAS  Google Scholar 

  25. Nakajima, T., Uchida, C., Anderson, S.F., Parvin, J.D. & Montminy, M. Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. Genes Dev. 11, 738–747 (1997).

    Article  CAS  Google Scholar 

  26. Brindle, P., Linke, S. & Montminy, M. Protein-kinase-A-dependent activator in transcription factor CREB reveals new role for CREM repressors. Nature 364, 821–824 (1993).

    Article  CAS  Google Scholar 

  27. Sisodia, S.S. Nuclear inclusions in glutamine repeat disorders: Are they pernicious, coincidental, or beneficial? Cell 95, 1–4 (1998).

    Article  CAS  Google Scholar 

  28. Li, X.-J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).

    Article  CAS  Google Scholar 

  29. Kalchman, M.A. et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nature Genet. 16, 44–53 (1997).

    Article  CAS  Google Scholar 

  30. Matilla, A. et al. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389, 974–978 (1997).

    Article  CAS  Google Scholar 

  31. Onodera, O. et al. Oligomerization of expanded-polyglutamine domain fluorescent fusion proteins in cultured mammalian cells. Biochem. Biophys. Res. Commun. 238, 599–605 (1997).

    Article  CAS  Google Scholar 

  32. Waragai, M. et al. PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. Hum. Mol. Genet. 8, 977–987 (1999).

    Article  CAS  Google Scholar 

  33. Gonzalez, G.A. & Montminy, M.R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989).

    Article  CAS  Google Scholar 

  34. Sapp, E. et al. Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington's disease using high resolution image analysis. Neuroscience 64, 397–404 (1995).

    Article  CAS  Google Scholar 

  35. Timmers, H.J.L.M., Swaab, D.F., van de Nes, J.A.P. & Kremer, H.P.H. Somatostatin 1-12 immunoreactivity is decreased in the hypothalamic lateral tuberal nucleus of Huntington's disease patients. Brain Res. 728, 141–148 (1996).

    Article  CAS  Google Scholar 

  36. De Souza, E.B., Whitehouse, P.J., Folstein, S.E., Price, D.L. & Vale, W.W. Corticotropin-releasing hormone (CRH) is decreased in the basal ganglia in Huntington's disease. Brain Res. 437, 355–359 (1987).

    Article  CAS  Google Scholar 

  37. Usdin, M.T., Shelbourne, P.F., Myers, R.M. & Madison, D.V. Impaired synaptic plasticity in mice carrying the Huntington's disease mutation. Hum. Mol. Genet. 8, 839–846 (1999).

    Article  CAS  Google Scholar 

  38. Li, S.-H., Cheng, A.L., Li, H. & Li, X.-J. Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J. Neurosci. 19, 5159–5172 (1999).

    Article  CAS  Google Scholar 

  39. Riccio, A., Ahn, S., Davenport, C.M., Blendy, J.A. & Ginty, D.D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358–2361 (1999).

    Article  CAS  Google Scholar 

  40. Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358–1362 (1999).

    Article  CAS  Google Scholar 

  41. Moulder, K.L., Onodera, O., Burke, J.R., Strittmatter, W.J. & Johnson, E.M. Jr Generation of neuronal intranuclear inclusions by polyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J. Neurosci. 19, 705–715 (1999).

    Article  CAS  Google Scholar 

  42. Perez, M.K. et al. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J. Cell Biol. 143, 1457–1470 (1998).

    Article  CAS  Google Scholar 

  43. Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. & Housman, D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl Acad. Sci. USA 96, 11404–11409 (1999).

    Article  CAS  Google Scholar 

  44. Gerber, H.P. et al. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263, 808–811 (1994).

    Article  CAS  Google Scholar 

  45. Schiestl, R.H. & Gietz, R.D. High efficiency transformation of intact yeast cells using single stranded nucleic acids as a carrier. Curr. Genet. 16, 339–346 (1989).

    Article  CAS  Google Scholar 

  46. Dignam, J.D., Lebovitz, R.M. & Roeder, R.G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11, 1475–1489 (1983).

    Article  CAS  Google Scholar 

  47. Parker, D. et al. Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism. Mol. Cell. Biol. 16, 694–703 (1996).

    Article  CAS  Google Scholar 

  48. Mizushima, S. & Nagata, S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 18, 5322 (1990).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Nagata for the pEF-BOS vector; E. Yaoita and H. Shimizu for use of the confocal imaging system; Y. Mishima and R. Kominami for advice on co-precipitation assays; and S. Maruyama for technical assistance. This study was supported in part by a grant from the Research for the Future Program from the Japan Society for the Promotion of Science (JSPS-RFTF96L00103), a Grant-in-Aid for Scientific Research on Priority Areas (Human Genome Program) from the Ministry of Education, Science, Sports and Culture, Japan, a grant from the Research Committee for Ataxic Diseases the Ministry of Health and Welfare, Japan, a grant for Surveys and Research on Specific Diseases, the Ministry of Health and Welfare, Japan, special coordination funds from the Japanese Science and Technology Agency, a grant for Research on Brain Science (H10-Brain-28) from the Ministry of Health and Welfare, Japan. This study was also supported in part by grants from Ministry of Education, Science, Culture, and Sports, Japan, Ministry of Health and Welfare, Japan, JST, Kanae Medical Foundation, Uehara Memorial Foundation, Naito Memorial Foundation, Yamanouchi memorial foundation, Santen Pharmaceutical Co. Ltd. and Kaken Pharmaceutical Co. Ltd.

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Authors and Affiliations

  1. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan

    Takayoshi Shimohata, Osamu Onodera, Satoshi Naruse, Tetsuya Kimura, Reiji Koide, Kenkichi Nozaki, Yasuteru Sano, Aki Sato, Takeshi Ikeuchi, Mutsuo Oyake, Toshiya Sato, Yasuyuki Aoyagi, Isao Hozumi & Shoji Tsuji

  2. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

    Mitsunori Yamada & Hitoshi Takahashi

  3. Institute of Applied Biochemistry, TARA Center, University of Tsukuba, Ibaraki, and PRESTO JST, Institute of Medical Science, St. Marianna University of Medicine, Kawasaki, Japan

    Toshihiro Nakajima & Takayuki Ooshima

  4. Department of Biochemistry, Hamamatsu University School of Medicine, Shizuoka, Japan

    Chiharu Uchida

  5. Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan

    Hiroshi Ishiguro & Toshiharu Nagatsu

  6. Department of Neurology, Jichi Medical School, Tochigi, Japan

    Kumi Sakoe, Yoshihisa Takiyama & Masatoyo Nishizawa

  7. Department of Neurology, Institute for Brain Research, Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Jun Goto & Ichiro Kanazawa

  8. Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, France

    Irwin Davidson

  9. Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, USA

    Naoko Tanese

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Correspondence to Shoji Tsuji.

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Shimohata, T., Nakajima, T., Yamada, M. et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26, 29–36 (2000). https://doi.org/10.1038/79139

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