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Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases

Item Type:Article
Title:Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases
Creators Name:Qi, M.L. and Tagawa, K. and Enokido, Y. and Yoshimura, N. and Wada, Y.I. and Watase, K. and Ishiura, S.I. and Kanazawa, I. and Botas, J. and Saitoe, M. and Wanker, E.E. and Okazawa, H.
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.
Keywords:Biological Models, Cell Death, Cultured Cells, HMGB1 Protein, HMGB2 Protein, Immunohistochemistry, Immunoprecipitation, Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry, Neurodegenerative Diseases, Neurons, Nuclear Proteins, Peptides, Protein Binding, Proteomics, Purkinje Cells, Signal Transduction, Small Interfering RNA, Two-Dimensional Gel Electrophoresis, Western Blotting, Wistar Rats, Animals, Drosophila, Rats
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:402-414
Date:April 2007
Official Publication:https://doi.org/10.1038/ncb1553
PubMed:View item in PubMed

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