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

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 mood and cognitive phenotypes at 2 months. From 3-4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibit 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 valuab...

本研究报道了一种新型亨廷顿舞蹈症（Huntington’s disease, HD）小鼠模型BAC226Q的构建与表征：该模型借助细菌人工染色体（bacterial artificial chromosome, BAC）系统构建，可表达携带约226个CAG-CAA重复序列的全长人类HTT基因，并包含内源性人类HTT启动子及调控元件。BAC226Q模型能够重现全谱系的年龄依赖性、进行性亨廷顿病样表型，且未出现非预期及异常表型。BAC226Q小鼠发育正常，并于2月龄时逐渐显现亨廷顿病样情绪与认知表型；3至4月龄阶段，该模型小鼠出现显著的进行性运动功能缺陷。至11月龄时，BAC226Q小鼠表现出寿命显著缩短、体重渐进性下降，并出现特征性神经病理改变，包括纹状体与皮层特异性脑萎缩、纹状体神经元死亡、广泛的亨廷顿蛋白聚集体形成以及反应性病理改变。综上，这款可重现稳健、年龄依赖性、进行性亨廷顿病样表型的新型BAC226Q小鼠，将成为极具价值的……