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Reduction of mutant ATXN1 rescues premature death in a conditional SCA1 mouse model
James P. Orengo, … , Harry T. Orr, Huda Y. Zoghbi
James P. Orengo, … , Harry T. Orr, Huda Y. Zoghbi
Published March 15, 2022
Citation Information: JCI Insight. 2022;7(8):e154442. https://doi.org/10.1172/jci.insight.154442.
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Resource and Technical Advance Genetics Neuroscience

Reduction of mutant ATXN1 rescues premature death in a conditional SCA1 mouse model

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that the cSCA1 mice produced less than half of the pathogenic protein compared with the unmodified SCA1 mice at 3 weeks of age. In contrast, restricted expression of the pathogenic SCA1 allele in motor neurons only led to a decreased distance traveled of mice in the open field assay and did not affect body weight or survival. We conclude that a 50% or greater reduction of the mutant protein has a dramatic effect on disease onset and progression; furthermore, we conclude that expression of polyglutamine-expanded ATXN1 at this level specifically in motor neurons is not sufficient to cause premature lethality.

Authors

James P. Orengo, Larissa Nitschke, Meike E. van der Heijden, Nicholas A. Ciaburri, Harry T. Orr, Huda Y. Zoghbi

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Figure 2

Mutant Atxn1 mRNA and protein levels at 3 weeks of age.

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Mutant Atxn1 mRNA and protein levels at 3 weeks of age.
Tissue was colle...
Tissue was collected from F1 progeny of cSCA1 × Sox2-Cre mice at 3 weeks of age. Specifically, cerebellum, brainstem, spinal cord, and tibialis anterior skeletal muscle were harvested and divided in half, with one half being used to extract RNA and the other half for protein extraction. For each genotype (WT, SCA1, or cSCA1 × Sox2-Cre [Sox2 cSCA1]), between 3 and 5 biological replicates were used. (A) qPCR was used to quantify mRNA expression of the Atxn1 gene. Statistical assessment performed using 1-way ANOVA, followed by Tukey’s multiple comparisons test **P < 0.01 and ****P < 0.0001. (B) Western blot was utilized to quantify protein levels of either WT ATXN1(2Q) or the polyglutamine expanded ATXN1(154Q) using the 11750 antibody. A representative Western blot is provided for each tissue region, followed by the full quantification of all samples in the bar graph below. ATXN1(2Q) statistical assessment performed using 1-way ANOVA followed by Tukey’s multiple comparisons test *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. ATXN1[154Q] statistical analysis was carried out with Student’s t test.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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