Abstract
Nuclear dysfunction is a key feature of the pathology of polyglutamine (polyQ) diseases. It has been suggested that mutant polyQ proteins impair functions of nuclear factors by interacting with them directly in the nucleus. However, a systematic analysis of quantitative changes in soluble nuclear proteins in neurons expressing mutant polyQ proteins has not been performed. Here, we perform a proteome analysis of soluble nuclear proteins prepared from neurons expressing huntingtin (Htt) or ataxin-1 (AT1) protein, and show that mutant AT1 and Htt similarly reduce the concentration of soluble high mobility group B1/2 (HMGB1/2) proteins. Immunoprecipitation and pulldown assays indicate that HMGBs interact with mutant AT1 and Htt. Immunohistochemistry showed that these proteins were reduced in the nuclear region outside of inclusion bodies in affected neurons. Compensatory expression of HMGBs ameliorated polyQ-induced pathology in primary neurons and in Drosophila polyQ models. Furthermore, HMGBs repressed genotoxic stress signals induced by mutant Htt or transcriptional repression. Thus, HMGBs may be critical regulators of polyQ disease pathology and could be targets for therapy development.
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Acknowledgements
This work was supported by grants to H.O. from the Japan Ministry of Education, Culture, Science, Sports and Technology (16650076), Japan Society for the Promotion of Science (JSPS; 16390249) and Japan Science and Technology Agency (JST; PRESTO). We thank M. Matsumoto and T. Miyashita (Tokyo Metropolitan Institute for Neuroscience, TMIN) for Drosophila experiments, T. Okuda and Shigeki Marubuchi (TMIN, Tokyo Medical and Dental University; TMDU) for primary culture, and T. Tajima for immunohistochemistry. We also thank H. Y. Zoghbi (Baylor College of Medicine) for sharing AT1 knock-in mouse samples and for critical reading of the manuscript.
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This work was mainly performed by M.-L.Q. in collaboration with K.T, Y.E. and other co-authors. The project was planned by H.O.
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Supplementary Figures S1, S2, S3, S4, S5, S6, S7 and Supplementary Methods (PDF 1509 kb)
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Qi, ML., Tagawa, K., Enokido, Y. et al. Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases. Nat Cell Biol 9, 402–414 (2007). https://doi.org/10.1038/ncb1553
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DOI: https://doi.org/10.1038/ncb1553
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