A novel and accurate full-length HTT mouse model for Huntington’s disease
Sushila A Shenoy,
Sushuang Zheng,
Wencheng Liu,
Yuanyi Dai,
Yuanxiu Liu,
Zhipeng Hou,
Susumu Mori,
Yi Tang,
Jerry Cheng,
Wenzhen Duan,
Chenjian Li
Affiliations
Sushila A Shenoy
Department of Neuroscience, Weill Cornell Graduate School of Medical Sciences, New York, United States
Sushuang Zheng
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Wencheng Liu
Department of Neuroscience, Weill Cornell Graduate School of Medical Sciences, New York, United States
Yuanyi Dai
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Yuanxiu Liu
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Zhipeng Hou
The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
Susumu Mori
The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
Yi Tang
Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China
Jerry Cheng
Department of Computer Science, New York Institute of Technology, New York, United States
Wenzhen Duan
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences; Solomon H.Snyder Department of Neuroscience, Johns Hopkins University School of medicine, Baltimore, United States
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.
