title: Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases.
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.
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors: Mei-Ling
authors: ML
authors: Qi
authors: Kazuhiko
authors: K
authors: Tagawa
authors: Yasushi
authors: Y
authors: Enokido
authors: Natsue
authors: N
authors: Yoshimura
authors: Yo-ichi
authors: Y
authors: Wada
authors: Kei
authors: K
authors: Watase
authors: Sho-ichi
authors: S
authors: Ishiura
authors: Ichiro
authors: I
authors: Kanazawa
authors: Juan
authors: J
authors: Botas
authors: Minoru
authors: M
authors: Saitoe
authors: Erich E
authors: EE
authors: Wanker
authors: Hitoshi
authors: H
authors: Okazawa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002478:Cells, Cultured; D004330:Drosophila; D015180:Electrophoresis, Gel, Two-Dimensional; D024243:HMGB1 Protein / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D024261:HMGB2 Protein / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D040901:Proteomics / Q000379:methods*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D024243:HMGB1 Protein; D024261:HMGB2 Protein; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; C097188:polyglutamine