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


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.

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Figure 1: Atxn1l associates with Atxn1; also shown here is a schematic representation of generation of Atxn1l duplication.
Figure 2: Atxn1l duplication suppresses Sca1154Q/+ cerebellar pathology.
Figure 3: Atxn1l enhances nuclear inclusion formation of polyglutamine-expanded Atxn1 in Purkinje cells and Neuro2A cells.
Figure 4: Elevated Atxn1l levels decrease the association of Atxn1[154Q] with CIC in cerebellar extracts.
Figure 5: Atxn1[154Q] is displaced from its larger endogenous complexes containing CIC as a result of Atxn1l duplication.
Figure 6: Proposed model for suppression of SCA1 pathology by the Atxn1l duplication.

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We are grateful to C.-C. Tsai (University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School) for providing ATXN1L antiserum; S. Vaishnav for mouse genotyping; A. McCall for isolating and characterizing Atxn1l clones; G. Schuster for ES cell work and generation of chimeric animals; K. Schulze for artwork (Fig. 6) and A. Flora, J. Lim, J. Gatchel, P. Moretti, E. Hyun and J. Crespo-Barreto for many discussions. This work was supported by the following US National Institutes of Health grants: National Institute for Neurological Disorders and Stroke grants NS27699 (to H.Y.Z.), NS22920 and NS45667 (to H.T.O.) and National Institute of Child Health and Human Development grant HD024064 (to the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center). A.B.B. was a postdoctoral fellow of the Hereditary Disease Foundation. H.Y.Z. is a Howard Hughes Medical Institute investigator.

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Authors and Affiliations



A.B. designed, performed or assisted in most of the experiments; analyzed data; characterized the Atxn1l duplication allele and wrote the manuscript. Y.L. performed ATXN1L immunoprecipitation experiments, identified the CIC protein interaction, designed and characterized the CIC antisera and edited the manuscript. P.J. designed and performed cerebellar Atxn1 immunoprecipitation experiments, characterized Atxn1l sera and provided critical commentary. H.C. designed and constructed the targeting construct. R.R. performed cerebellar extraction, protein blots and HPLC chromatography and characterized Atxn1l sera. R.S. performed the in situ hybridization experiments. J.F. performed cerebellar CIC immunoprecipitation experiments, provided critical commentary and edited the manuscript. J.K. made the ATXN1L cDNA expression vector. H.O. assisted in data analysis and interpretation. H.Z. led the project by inspiring the search for ATXN1 paralogs, generated major hypotheses and formulated the genetic and biochemical experiments, interpreted data, provided experimental direction and edited the manuscript.

Corresponding author

Correspondence to Huda Y Zoghbi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Atxn1l expression in Purkinje cells of adult mouse cerebellum. (PDF 527 kb)

Supplementary Fig. 2

Fractionation of ATXN1L, ATXN1 and CIC by gel filtration chromatography of mouse cerebellar extracts. (PDF 176 kb)

Supplementary Fig. 3

ATXN1 and ATXN1L compete for interaction with CIC. (PDF 106 kb)

Supplementary Fig. 4

Atxn1l duplication suppresses Sca1154Q/+ cerebellar pathology. (PDF 735 kb)

Supplementary Fig. 5

Atxn1l duplication suppresses Sca1154Q/+ lethality. (PDF 341 kb)

Supplementary Fig. 6

ATXN1L levels are similar between wild-type and Sca1154Q/+ animals. (PDF 131 kb)

Supplementary Table 1

ANOVA post hoc pairwise comparisons. (PDF 55 kb)

Supplementary Methods (PDF 52 kb)

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Bowman, A., Lam, Y., Jafar-Nejad, P. et al. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet 39, 373–379 (2007).

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