Atrophin-1, the Dentato-rubral and Pallido-luysian Atrophy Gene Product, Interacts with ETO/MTG8 in the Nuclear Matrix and Represses Transcription

doi:10.1083/jcb.150.5.939

Published online 5 September 2000. doi:10.1083/jcb.150.5.939

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© The Rockefeller University Press, 0021-9525/2000/9/939/ $5.00
The Journal of Cell Biology, Volume 150, Number 5, September 4, 2000 939-948

Original Article

Atrophin-1, the Dentato-rubral and Pallido-luysian Atrophy Gene Product, Interacts with ETO/MTG8 in the Nuclear Matrix and Represses Transcription

Jonathan D. Wood^a, Frederick C. Nucifora, Jr.^a, Kui Duan^a, Chuanyi Zhang^a, Jianxiang Wang^d, Yujin Kim^a, Gabriele Schilling^a, Nicoletta Sacchi^e, Johnson M. Liu^d, and Christopher A. Ross^a,b,c
^a Division of Neurobiology, Department of Psychiatry, the
^b Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
^c Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
^d Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892
^e Department of Biology and Genetics, School of Medicine, University of Milan, Milan, Italy 20133

Correspondence to: Jonathan D. Wood, The Johns Hopkins University School of Medicine, Department of Psychiatry, 720 Rutland Ave., Ross 618, Baltimore, MD 21205-2196. Tel:(410) 614-0011 Fax:(410) 614-0013 E-mail:jonwood{at}jhmi.edu.

Dentato-rubral and pallido-luysian atrophy (DRPLA) is one ofthe family of neurodegenerative diseases caused by expansionof a polyglutamine tract. The drpla gene product, atrophin-1,is widely expressed, has no known function or activity, andis found in both the nuclear and cytoplasmic compartments ofneurons. Truncated fragments of atrophin-1 accumulate in neuronalnuclei in a transgenic mouse model of DRPLA, and may underliethe disease phenotype.

Using the yeast two-hybrid system, we identified ETO/MTG8, acomponent of nuclear receptor corepressor complexes, as an atrophin-1–interactingprotein. When cotransfected into Neuro-2a cells, atrophin-1and ETO/MTG8 colocalize in discrete nuclear structures thatcontain endogenous mSin3A and histone deacetylases. These structuresare sodium dodecyl sulfate–soluble and associated withthe nuclear matrix. Cotransfection of ETO/MTG8 with atrophin-1recruits atrophin-1 to the nuclear matrix, while atrophin-1and ETO/MTG8 cofractionate in nuclear matrix preparations frombrains of DRPLA transgenic mice. Furthermore, in a cell transfection–basedassay, atrophin-1 represses transcription. Together, these resultssuggest that atrophin-1 associates with nuclear receptor corepressorcomplexes and is involved in transcriptional regulation.

Emerging links between disease-associated polyglutamine proteins,nuclear receptors, translocation-leukemia proteins, and thenuclear matrix may have important repercussions for the pathobiologyof this family of neurodegenerative disorders.

Key Words: trinucleotide repeats, neurodegenerative diseases, cerebellarnuclei, nuclear matrix, myeloid leukemia

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