title: Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription.
abstract: Dentato-rubral and pallido-luysian atrophy (DRPLA) is one of the family of neurodegenerative diseases caused by expansion of a polyglutamine tract. The drpla gene product, atrophin-1, is widely expressed, has no known function or activity, and is found in both the nuclear and cytoplasmic compartments of neurons. Truncated fragments of atrophin-1 accumulate in neuronal nuclei in a transgenic mouse model of DRPLA, and may underlie the disease phenotype. Using the yeast two-hybrid system, we identified ETO/MTG8, a component of nuclear receptor corepressor complexes, as an atrophin-1-interacting protein. When cotransfected into Neuro-2a cells, atrophin-1 and ETO/MTG8 colocalize in discrete nuclear structures that contain endogenous mSin3A and histone deacetylases. These structures are sodium dodecyl sulfate-soluble and associated with the nuclear matrix. Cotransfection of ETO/MTG8 with atrophin-1 recruits atrophin-1 to the nuclear matrix, while atrophin-1 and ETO/MTG8 cofractionate in nuclear matrix preparations from brains of DRPLA transgenic mice. Furthermore, in a cell transfection-based assay, atrophin-1 represses transcription. Together, these results suggest that atrophin-1 associates with nuclear receptor corepressor complexes and is involved in transcriptional regulation. Emerging links between disease-associated polyglutamine proteins, nuclear receptors, translocation-leukemia proteins, and the nuclear matrix may have important repercussions for the pathobiology of this family of neurodegenerative disorders.
authors.affiliation: Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jonwood@jhmi.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Wood
authors.forename: F C
authors.initials: FC
authors.lastname: Nucifora
authors.forename: K
authors.initials: K
authors.lastname: Duan
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.forename: G
authors.initials: G
authors.lastname: Schilling
authors.forename: N
authors.initials: N
authors.lastname: Sacchi
authors.forename: J M
authors.initials: JM
authors.lastname: Liu
authors.forename: C A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000818:Animals; D001284:Atrophy; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005917:Globus Pallidus / Q000473:pathology*; D006655:Histone Deacetylases / Q000032:analysis / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015530:Nuclear Matrix / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D011994:Recombinant Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; C095278:atrophin-1; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex