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: J D Wood, F C Nucifora Jr, K Duan, C Zhang, J Wang, Y Kim, G Schilling, N Sacchi, J M Liu, C A Ross
• Journal: The Journal of cell biology (J Cell Biol) Vol. 150 Issue 5 Pg. 939-48 (Sep 04 2000) ISSN: 0021-9525 [Print] United States
• PMID: 10973986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Nerve Tissue Proteins
• Peptide Fragments
• Proto-Oncogene Proteins
• RUNX1 Translocation Partner 1 Protein
• RUNX1T1 protein, human
• Recombinant Proteins
• Repressor Proteins
• SIN3A transcription factor
• Transcription Factors
• atrophin-1
• Histone Deacetylases
• Sin3 Histone Deacetylase and Corepressor Complex

Topics

• Animals
• Atrophy
• Cloning, Molecular
• DNA-Binding Proteins (metabolism)
• Globus Pallidus (pathology)
• Histone Deacetylases (analysis, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Matrix (metabolism, ultrastructure)
• Peptide Fragments (metabolism)
• Proto-Oncogene Proteins
• RUNX1 Translocation Partner 1 Protein
• Recombinant Proteins (metabolism)
• Repressor Proteins (analysis, metabolism)
• Sin3 Histone Deacetylase and Corepressor Complex
• Transcription Factors (metabolism)
• Transcription, Genetic
• Transfection
• Tumor Cells, Cultured