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

Huda Y Zoghbi,Larissa Nitschke,Nicholas A Ciaburri,James P Orengo,Meike E Van Der Heijden,Harry T Orr

doi:10.1172/jci.insight.154442

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.

Highlights

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease with a typical age of onset in the 30s and initial symptoms consisting of cerebellar ataxia and poor motor coordination [1]
We discuss the generation of our conditional SCA1 (cSCA1) mouse model and find that polyglutamine-expanded ATXN1 levels from the conditional mutant allele are reduced by more than half of those compared with the nonconditional polyglutamine– expanded ATXN1
While this finding was unexpected, we discovered, as the mice aged, that it allowed for a unique possibility: we could examine the effect of significantly reducing mutant ATXN1 levels on disease onset and progression

Summary

Introduction

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease with a typical age of onset in the 30s and initial symptoms consisting of cerebellar ataxia and poor motor coordination [1]. This disease is caused by a trinucleotide (CAG) repeat expansion in the first coding exon of the gene ATXN1 [2, 3]. Weakness in the muscles supporting breathing and safe swallowing is an established major contributor to the development of aspiration pneumonia in a diverse array of neurological disorders Motor neurons regulate these activities, and when they degenerate, such as in amyotrophic lateral sclerosis (ALS), individuals suffer from premature death by the same respiratory complications as those seen in SCA1 [10]

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Conclusion