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Abstract
Spinocerebellar ataxia type 7 (SCA7) is a debilitating neurodegenerative disease caused by expansion of a polyglutamine [poly(Q)] tract in ATXN7, a subunit of the deubiquitinase (DUB) module (DUBm) in the SAGA complex. The effects of ATXN7-poly(Q) on DUB activity are not known. To address this important question, we reconstituted the DUBm in vitro with either wild-type ATXN7 or a pathogenic form, ATXN7-92Q NT, with 92 Q residues at the N terminus (NT). We found that both forms of ATXN7 greatly enhance DUB activity but that ATXN7-92Q NT is largely insoluble unless it is incorporated into the DUBm. Cooverexpression of DUBm components in human astrocytes also promoted the solubility of ATXN7-92Q, inhibiting its aggregation into nuclear inclusions that sequester DUBm components, leading to global increases in ubiquitinated H2B (H2Bub) levels. Global H2Bub levels were also increased in the cerebellums of mice in a SCA7 mouse model. Our findings indicate that although ATXN7 poly(Q) expansions do not change the enzymatic activity of the DUBm, they likely contribute to SCA7 by initiating aggregates that sequester the DUBm away from its substrates.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01454-14.
ACKNOWLEDGMENTS
We thank Boyko Atanassov for many helpful discussions on this project, Didier Devys for ATXN7L3 and ENY2 cDNAs, and Huda Zoghbi for providing the SCA7 mouse model.
This work was supported by a research training award from the Cancer Prevention and Research Institute of Texas (CPRIT RP140106) to A.C.S. and by NIH grant 1R01-GM096472 to S.Y.R.D.