University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Mol Brain. 2023 Sep 19;16(1):67. doi: 10.1186/s13041-023-01054-6.
Huntington's Disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment due to the expansion of a polyglutamine (CAG) repeat in the N-terminal region of the huntingtin (Htt) protein. The creation of HD mouse models represents a critical step in the research for HD treatment. Among the currently available HD mouse models, the zQ175 knock-in mouse line is the first to display robust disease phenotype on a heterozygous background. The newer FDNQ175 mouse model is derived from the zQ175 mouse line and presents a more aggressive phenotype. Moreover, increasing evidence has implicated sex as a contributing factor in the progression of HD symptoms. Here, we compared the progression of HD phenotypes in male and female heterozygous FDNQ175 mice. We found that both male and female heterozygous mice showed deficits in forelimb grip strength and cognition as early as 6 months of age. However, female FDNQ175 mice were less vulnerable to HD-associated decline in limb coordination and movement. Neither male nor female FDNQ175 mice exhibited reduced locomotor activity in the open field or exhibit consistent differences in anxiety at 6-12 months of age. Both male and female FDNQ175 mice exhibited increased numbers of huntingtin aggregates with age and 8-month-old female FDNQ175 mice had significantly more aggregates than their male counterparts. Taken together, our results provide further evidence that sex can influence the progression of HD phenotype in preclinical animal models and must be taken into consideration for future HD research.
亨廷顿病（HD）是一种遗传性常染色体显性神经退行性疾病，由于亨廷顿（Htt）蛋白 N 端区域内的多聚谷氨酰胺（CAG）重复扩展，导致进行性运动和认知障碍。创建 HD 小鼠模型是 HD 治疗研究的关键步骤。在目前可用的 HD 小鼠模型中，zQ175 敲入鼠系是第一个在杂合背景下显示出稳健疾病表型的模型。更新的 FDNQ175 小鼠模型源自 zQ175 鼠系，表现出更具侵袭性的表型。此外，越来越多的证据表明，性别是影响 HD 症状进展的一个因素。在这里，我们比较了雄性和雌性杂合 FDNQ175 小鼠中 HD 表型的进展。我们发现，雄性和雌性杂合小鼠在 6 个月大时就表现出前肢握力和认知缺陷。然而，雌性 FDNQ175 小鼠对与 HD 相关的肢体协调和运动能力下降的敏感性较低。雄性或雌性 FDNQ175 小鼠在 6-12 个月大时均未表现出运动活性降低或焦虑程度的一致差异。雄性和雌性 FDNQ175 小鼠随年龄增长均表现出亨廷顿蛋白聚集体数量增加，8 月龄雌性 FDNQ175 小鼠的聚集体数量明显多于雄性。总之，我们的结果进一步证明，性别可以影响临床前动物模型中 HD 表型的进展，在未来的 HD 研究中必须考虑到这一点。
