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Published online 4 September 2000. doi:10.1083/jcb.150.5.939
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© The Rockefeller University Press, 0021-9525/2000//939 $5.00
The Journal of Cell Biology, Volume 150, Number 5, , 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. Wooda, Frederick C. Nucifora, Jr.a, Kui Duana, Chuanyi Zhanga, Jianxiang Wangd, Yujin Kima, Gabriele Schillinga, Nicoletta Sacchie, Johnson M. Liud, and Christopher A. Rossa,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
The Johns Hopkins University School of Medicine, Department of Psychiatry, 720 Rutland Ave., Ross 618, Baltimore, MD 21205-2196.(410) 614-0013(410) 614-0011

jonwood{at}jhmi.edu

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.

Key Words: trinucleotide repeats • neurodegenerative diseases • cerebellar nuclei • nuclear matrix • myeloid leukemia

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CBP, CREB-binding protein; DBD, DNA-binding domain; DRPLA, dentato-rubral and pallido-luysian atrophy; ETO, product of eight-twenty-one myeloid translocation gene on chromosome 8; HDAC, histone deacetylase; MTG8, product of myeloid translocation gene on chromosome 8; MTG16, product of myeloid translocation gene on chromosome 16; MTGR1, MTG8-related protein 1; N-CoR, nuclear receptor corepressor; PML, promyelocytic leukemia protein; POD, promyelocytic leukemia antigen oncogenic domain; SMRT, silencing mediator for retinoid and thyroid hormone receptors; VRC, vanadyl ribonucleoside complex.


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