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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 3

Cell type–specific restriction of the pathogenic polyglutamine–expanded ATXN1 protein defined by Cre driver.

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Cell type–specific restriction of the pathogenic polyglutamine–expanded ...
Tissue was harvested between 36 and 48 weeks of age from cSCA1 mice and F1 offspring from cSCA1 mice crossed with various Cre lines: Sox2 (ubiquitous), ChAT (motor neuron), Ckm (skeletal muscle), and Pcp2 (Purkinje neuron). Specifically, hippocampal CA1 neurons, cerebellar Purkinje neurons, cervical spinal cord motor neurons, and tibialis anterior skeletal muscle cells were imaged after staining with the ATXN1 11NQ antibody. Yellow arrows indicate nuclei with ATXN1 aggregate formation. Nuclear inclusions of ATXN1 protein occurs only in the presence of the polyglutamine expansion; thus, these inclusions are used as a proxy for expression of the recombined pathogenic allele. All images were taken with a 40× objective and then digitally zoomed to allow for optimal visualization of the nuclear inclusions. Scale bars: 50 μm.

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