Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice.

Publication date: Feb 06, 2020

Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse huntingtin gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.

Yang, S., Yang, H., Huang, L., Chen, L., Qin, Z., Li, S., and Li, X.J. Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice. 06920. 2020 Proc Natl Acad Sci U S A.

Concepts Keywords
Cas9 Nonpolyglutamine products
CRISPR Branches of biology
Endogenous Immune system
Genome Editing Huntington’s disease
Huntingtin Autosomal dominant disorders
Huntington Molecular biology
Mice Neurodegeneration
Neuropathological Huntingtin
Pathogenesis Cas9
Peptides CRISPR
Phenotypes Genome editing
Sci Androgen receptor


Type Source Name
drug DRUGBANK Ranitidine


Original Article

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