Abstract
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1335-1347 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 127 |
| Issue number | 7 |
| DOIs | |
| State | Published - Dec 29 2006 |
Bibliographical note
Funding Information:We are grateful to Yuchun He for generating the Cic transgenic fruit flies, to Christina Thaller for in situ hybridization, to Bobby Antalffy for immunohistochemistry, to Sukeshi Vaishnav for mouse genotyping, to Jordi Casanova for providing Drosophila cic flies and cDNA constructs, and to Dong Zhang for providing reagents and advice for TAP. Special thanks to Hugo Bellen, Hamed Jafar-Nejad, Patrik Verstreken, Adriano Flora, Jennifer Gatchel, Paolo Moretti, and Juan Crespo-Barreto for many insightful discussions and Vicky Brandt for editorial input. This work was supported by NINDS NS27699 (to H.Y.Z.), NS22920 and NS45667 (to H.T.O.), and NICHD HD024064 (to the BCM-MRRC). A.B.B. was a Postdoctoral Fellow of the Hereditary Disease Foundation. H.Y.Z. is an HHMI investigator.