Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice

• Type of Material: Article
• Authors: Qiong Liu, Emory University; Siying Cheng, Central South University; Huiming Yang, Emory University; Louyin Zhu, Emory University; Yongcheng Pan, Emory University; Liang Jing, Huazhong University of Science & Technology; Beisha Tang, Central South University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2020-08-18
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2020 National Academy of Science. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2002283117
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences of the United States
• Volume: 117
• Issue: 33
• Start Page: 20265
• End Page: 20273
• Grant/Funding Information: This work was supported by grants from the NIH (R01 NS036232 and R01 NS101701), National Natural Science Foundation of China (81830032, 31872779, 81701281, and 2016YFC1306000), Key Field Research and Development Program of Guangdong province (2018B030337001), and Guangdong Key Laboratory of nonhuman primate models of brain diseases.
• Keywords: In mouse model; Binding; neurodegeneration; Science & Technology; Brain; Aggregation; Mutant Huntington; Expression; huntingtin-associated protein; sumoylation; Multidisciplinary Sciences; RHES; Protein; aggregates; Neurotoxicity; Science & Technology - Other Topics; polyglutamine; Neuronal death
• Research Categories: Biology, Genetics; Biology, Neuroscience; Engineering, Biomedical

Abstract

Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.