A novel and accurate full-length HTT mouse model for Huntington’s disease

eLife

Jerry Cheng¹  Sushila A Shenoy²  Wencheng Liu²  Wenzhen Duan³  Yi Tang⁴  Yuanyi Dai⁵  Yuanxiu Liu⁵  Sushuang Zheng⁵  Chenjian Li⁵  Susumu Mori⁶  Zhipeng Hou⁶ 

[1] Department of Computer Science, New York Institute of Technology, New York, United States;Department of Neuroscience, Weill Cornell Graduate School of Medical Sciences, New York, United States;Division of Neurobiology, Department of Psychiatry and Behavioral Sciences; Solomon H.Snyder Department of Neuroscience, Johns Hopkins University School of medicine, Baltimore, United States;Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China;The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China;The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States;

关键词: huntington's disease;    neurodegeneration;    transgenic mouse;    brain atrophy;    neuron loss;    Htt aggregates;    Huntington’s disease;    Human BAC;    Body weight loss;    Htt aggregates;   

DOI  :  10.7554/eLife.70217

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.

【 授权许可】

CC BY