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

• Type of Material: Article
• Authors: Su Yang, Jinan University; Huiming Yang, Sun Yat-sen University; Luoxiu Huang, Emory University; Luxiao Chen, Emory University; Zhaohui Qin, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2020-02-25
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2020. Published under the PNAS license.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1919197117
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 117
• Issue: 8
• Start Page: 4411
• End Page: 4417
• Grant/Funding Information: This work was supported by the NIH (Grants R01NS101701, R01NS095279) and the National Natural Science Foundation of China (Grant 81830032).
• Keywords: Huntington’s disease; CAG repeat; aggregates; gene targeting; neurodegeneration

Abstract

Repeat-associated non-AUG (RAN) translation enables protein translation independent of an AUG start codon. Previous studies identified RAN-translated products in cellular models of CAG repeat expansion diseases, including Huntington’s disease (HD). However, whether RAN-translated products, when expressed at the endogenous level, truly contribute to disease pathogenesis remains unknown. In the present study, we established knock-in mouse models for HD, which enable the expression of mutant Huntingtin (HTT) and RAN-translated products or only RAN-translated products at endogenous levels. We were unable to detect RAN-translated products in these mouse models, and found only the mouse model that expresses expanded polyQ peptides showed HD pathological phenotypes, suggesting that RAN-translated products do not critically contribute to HD pathogenesis.