RRC ID 60789
Author Qi ML, Tagawa K, Enokido Y, Yoshimura N, Wada Y, Watase K, Ishiura S, Kanazawa I, Botas J, Saitoe M, Wanker EE, Okazawa H.
Title Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases.
Journal Nat Cell Biol
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.
Volume 9(4)
Pages 402-14
Published 2007-4
DOI 10.1038/ncb1553
PII ncb1553
PMID 17384639
MeSH Animals Blotting, Western Cell Death Cells, Cultured Drosophila Electrophoresis, Gel, Two-Dimensional HMGB1 Protein / analysis HMGB1 Protein / metabolism HMGB1 Protein / physiology* HMGB2 Protein / analysis HMGB2 Protein / metabolism HMGB2 Protein / physiology* Immunohistochemistry Immunoprecipitation Models, Biological Neurodegenerative Diseases / genetics Neurodegenerative Diseases / metabolism* Neurodegenerative Diseases / pathology Neurons / cytology Neurons / metabolism Nuclear Proteins / analysis Nuclear Proteins / metabolism Nuclear Proteins / physiology* Peptides / genetics Peptides / metabolism Protein Binding Proteomics / methods* Purkinje Cells / cytology Purkinje Cells / metabolism RNA, Small Interfering Rats Rats, Wistar Signal Transduction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Times Cited 68