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

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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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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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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