Reduction of Mutant ATXN1 Rescues Premature Death in a Conditional SCA1 Mouse Model

Authors

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

Publication Date

4-22-2022

Journal

JCI Insight

DOI

10.1172/jci.insight.154442

PMID

35290244

PMCID

PMC9089789

PubMedCentral® Posted Date

4-22-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Ataxin-1, Disease Models, Animal, Mice, Mortality, Premature, Motor Neurons, Spinocerebellar Ataxias, Genetics, Neuroscience, Mouse models, Movement disorders, Neurodegeneration

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.