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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 1

Generation of a conditional SCA1 mouse model.

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Generation of a conditional SCA1 mouse model.
(A) Construct design illus...
(A) Construct design illustrating the targeted location of the flox-stop-flox cassette knock-in using CRISPR/Cas9 tools. The location of the knock-in is in the intron upstream of the first coding exon (exon 7) in the endogenous mouse Atxn1 gene. Specifically, the allele encoding the expanded CAG repeat tract was targeted for knock-in. (B) Reverse transcriptase PCR from primary fibroblast–derived SCA1 and cSCA1 mice. Cells were either electroporated with empty vector or a vector expressing Cre recombinase. cSCA1 cells selectively expressed the expanded CAG repeat allele in the presence of Cre recombinase.

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