ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology

Yung C. Lam, Aaron B. Bowman, Paymaan Jafar-Nejad, Janghoo Lim, Ronald Richman, John D. Fryer, Eric D. Hyun, Lisa A. Duvick, Harry T. Orr, Juan Botas, Huda Y. Zoghbi

Research output: Contribution to journalArticle

197 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1335-1347
Number of pages13
JournalCell
Volume127
Issue number7
DOIs
StatePublished - Dec 29 2006
Externally publishedYes

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Spinocerebellar Ataxias
Proteins
Neurodegenerative diseases
Neurodegenerative Diseases
Cerebellum
Drosophila
Cells
Mutation
Neuropathology

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., ... Zoghbi, H. Y. (2006). ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology. Cell, 127(7), 1335-1347. https://doi.org/10.1016/j.cell.2006.11.038

ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology. / Lam, Yung C.; Bowman, Aaron B.; Jafar-Nejad, Paymaan; Lim, Janghoo; Richman, Ronald; Fryer, John D.; Hyun, Eric D.; Duvick, Lisa A.; Orr, Harry T.; Botas, Juan; Zoghbi, Huda Y.

In: Cell, Vol. 127, No. 7, 29.12.2006, p. 1335-1347.

Research output: Contribution to journalArticle

Lam, YC, Bowman, AB, Jafar-Nejad, P, Lim, J, Richman, R, Fryer, JD, Hyun, ED, Duvick, LA, Orr, HT, Botas, J & Zoghbi, HY 2006, 'ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology', Cell, vol. 127, no. 7, pp. 1335-1347. https://doi.org/10.1016/j.cell.2006.11.038
Lam, Yung C. ; Bowman, Aaron B. ; Jafar-Nejad, Paymaan ; Lim, Janghoo ; Richman, Ronald ; Fryer, John D. ; Hyun, Eric D. ; Duvick, Lisa A. ; Orr, Harry T. ; Botas, Juan ; Zoghbi, Huda Y. / ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology. In: Cell. 2006 ; Vol. 127, No. 7. pp. 1335-1347.
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