Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription

Dentato-rubral and pallido-luysian atrophy (DRPLA) is one of the family of neurodegenerative diseases caused by expansion of a polyglutamine tract. Th e drp1a gene product, atrophin-1, is widely expressed, has no known functio n or activity, and is found in both the nuclear and cytoplasmic compartment s of neurons. Truncated fragments of atrophin-1 accumulate in neuronal nucl ei in a transgenic mouse model of DRPLA, and may underlie the disease pheno type. Using the yeast two-hybrid system, we identified ETO/MTG8, a component of n uclear receptor corepressor complexes, as an atrophin-1-interacting protein . When cotransfected into Neuro-2a cells, atrophin-1 and ETO/MTG8 colocaliz e in discrete nuclear structures that contain endogenous mSin3A and histone deacetylases. These structures are sodium dodecyl sulfate-soluble and asso ciated with the nuclear matrix. Cotransfection of ETO/MTG8 with atrophin-1 recruits atrophin-1 to the nuclear matrix, while atrophin-1 and ETO/MTG8 co fractionate 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 transcriptio nal regulation. Emerging links between disease-associated polyglutamine proteins, nuclear r eceptors, translocation-leukemia proteins, and the nuclear matrix may have important repercussions for the pathobiology of this family of neurodegener ative disorders.