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

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

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4 Scopus citations


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.

Original languageEnglish (US)
Article numbere154442
JournalJCI Insight
Issue number8
StatePublished - Apr 22 2022

Bibliographical note

Funding Information:
We thank the Genetically Engineered Rodent Models Core at Baylor College of Medicine for guidance in sgRNA design and technical assistance of CRISPR injections to produce the conditional SCA1 mouse model. Special thanks, in particular, to Denise Lanza for her extensive advice and hands-on assistance. Work performed by this Core was supported, in part, by funding from NIH/NCI grant P30 CA125123 to the Dan L Duncan Comprehensive Cancer Center. In addition, we thank the Intellectual and Development Disabilities Research Center (IDDRC) neuropathology, animal behavior, and in situ hybridization cores and at the Jan and Dan Duncan Neurological Research Institute within Texas Children’s Hospital for assistance with preparation of tissue sections, supported by funding from the NICHHD/NIH (U54HD083092. Funding support for this work comes from the NINDS/NIH (K08 NS102396), Chao Physician Scientist Award (BCM), Clifford Elder White Graham Endowed Research Fund (BCM), and the National Ataxia Foundation Young Investigator Award for JPO. A postdoctoral award from the Dystonia Medical Research Foundation supported MEVDH. Additional support was provided by the NINDS/NIH (R37 NS027699), the BCM IDDRC funded through the NICHHD/NIH (U54HD083092), and the Howard Hughes Medical Institute (HHMI) to HYZ.

Publisher Copyright:
Copyright: © 2022, Orengo et al.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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