Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, Vancouver, BC, Canada.
Division of Neurology, Department of Medicine, University of British Columbia Hospital, Wesbrook Mall, Vancouver, BC, Canada.
Hum Mol Genet. 2019 May 15;28(10):1661-1670. doi: 10.1093/hmg/ddz009.
Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene and is characterized by early and selective striatal neurodegeneration. The huntingtin (HTT) protein is ubiquitously expressed in many tissues and the cellular pathogenesis of the disease is not fully understood. Immune cell dysfunction due to mutant HTT (mHTT) expression and aberrant immune system activation in HD patients suggests that inflammatory processes may contribute to HD pathogenesis. Here we used the BACHD mouse model of HD, which carries a conditional transgene expressing full-length human mHTT, to selectively deplete mHTT expression in myeloid lineage cells, including microglia, and evaluated the effects on HD-related behavior and neuropathology. In the converse experiment, we depleted mHTT expression in the majority of cells in the brain but specifically excluding microglia and again evaluated behavior and neuropathology. In mice with myeloid-specific mHTT-depletion, we observed no significant rescue of any behavioral or neuropathological outcome measures, while neural-specific knockout mice showed significant rescue of body weight, rotarod performance and striatal volume. We conclude that mHTT expression in microglia, though clearly affecting specific aspects of microglia function, does not alter disease pathogenesis in the BACHD mouse model. This may have implications for current or future therapeutic trials testing immune-modulating drugs in HD patients.
亨廷顿病（HD）是由 HTT 基因中的 CAG 重复扩展引起的，其特征是早期和选择性纹状体神经退行性变。亨廷顿蛋白（HTT）在许多组织中广泛表达，疾病的细胞发病机制尚不完全清楚。由于突变 HTT（mHTT）表达和 HD 患者异常的免疫系统激活导致免疫细胞功能障碍，表明炎症过程可能有助于 HD 的发病机制。在这里，我们使用了 BACHD 小鼠模型，该模型携带一个表达全长人 mHTT 的条件转基因，选择性地耗尽髓系细胞（包括小胶质细胞）中的 mHTT 表达，并评估了其对 HD 相关行为和神经病理学的影响。在相反的实验中，我们耗尽了大脑中大多数细胞但不包括小胶质细胞的 mHTT 表达，并再次评估了行为和神经病理学。在髓系特异性 mHTT 耗竭的小鼠中，我们没有观察到任何行为或神经病理学测量结果的显著改善，而神经特异性敲除小鼠则表现出体重、旋转棒性能和纹状体体积的显著改善。我们得出结论，小胶质细胞中的 mHTT 表达虽然明显影响小胶质细胞功能的特定方面，但不会改变 BACHD 小鼠模型中的疾病发病机制。这可能对目前或未来的临床试验测试 HD 患者的免疫调节药物具有重要意义。
