Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes

Aaron B. Bowman, Yung C. Lam, Paymaan Jafar-Nejad, Hung Kai Chen, Ronald Richman, Rodney C. Samaco, John D. Fryer, Juliette J. Kahle, Harry T. Orr, Huda Y. Zoghbi

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.

Original languageEnglish (US)
Pages (from-to)373-379
Number of pages7
JournalNature Genetics
Volume39
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

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Spinocerebellar Ataxias
Glutamine
Neurodegenerative Diseases
Ships
polyglutamine
Ataxin-1
Neuropathology
Pathology
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Bowman, A. B., Lam, Y. C., Jafar-Nejad, P., Chen, H. K., Richman, R., Samaco, R. C., ... Zoghbi, H. Y. (2007). Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nature Genetics, 39(3), 373-379. https://doi.org/10.1038/ng1977

Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. / Bowman, Aaron B.; Lam, Yung C.; Jafar-Nejad, Paymaan; Chen, Hung Kai; Richman, Ronald; Samaco, Rodney C.; Fryer, John D.; Kahle, Juliette J.; Orr, Harry T.; Zoghbi, Huda Y.

In: Nature Genetics, Vol. 39, No. 3, 03.2007, p. 373-379.

Research output: Contribution to journalArticle

Bowman, AB, Lam, YC, Jafar-Nejad, P, Chen, HK, Richman, R, Samaco, RC, Fryer, JD, Kahle, JJ, Orr, HT & Zoghbi, HY 2007, 'Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes', Nature Genetics, vol. 39, no. 3, pp. 373-379. https://doi.org/10.1038/ng1977
Bowman, Aaron B. ; Lam, Yung C. ; Jafar-Nejad, Paymaan ; Chen, Hung Kai ; Richman, Ronald ; Samaco, Rodney C. ; Fryer, John D. ; Kahle, Juliette J. ; Orr, Harry T. ; Zoghbi, Huda Y. / Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. In: Nature Genetics. 2007 ; Vol. 39, No. 3. pp. 373-379.
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