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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 6

Behavioral effects of cell type–specific restriction of polyglutamine-expanded ATXN1 protein.

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Behavioral effects of cell type–specific restriction of polyglutamine-ex...
(A) SCA1 mice and F1 offspring of cSCA1 mice crossed with various Cre lines: Sox2 (ubiquitous), ChAT (motor neuron), Ckm (skeletal muscle), and Pcp2 (Purkinje neuron) were subjected to open field assay at 7 or 15 weeks of age, respectively. Total distance traveled in cm during the assay was plotted. W) indicates either WT or Cre alone mice, and cSCA1 indicates Cre × cSCA1 mice. SCA1 group: WT, n = 22; SCA1, n = 22. ***P < 0.001 with t test. Sox2 group: WT, n = 20; cSCA1, n = 15. **** P < 0.0001 with t test. ChAT group: WT, n = 16; cSCA1, n = 15. **P < 0.01 with t test. Ckm group: WT, n = 13; cSCA1, n = 13. P > 0.05 with t test. Pcp2 group: WT, n = 20; cSCA1, n = 19. P > 0.05 with t test. (B) Retention time on an accelerating rotating rod was measured in SCA1 and cSCA1 mice crossed with various Cre lines at 7 or 11 weeks of age, respectively. SCA1 group: WT, n = 22; SCA1, n = 22. Sox2 group: WT, n = 20; cSCA1, n = 16. ChAT group: WT, n = 17; cSCA1, n = 13. Ckm group: WT, n = 13; cSCA1, n = 13. Pcp2 group: WT, n = 16; cSCA1, n = 13. For each pair, a 2-way ANOVA was calculated with Sidak’s multiple comparisons test, *P < 0.05, **P < 0.01, and ****P < 0.0001.

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