The R6/2 transgenic mouse model of Huntington’s disease (HD) carries several copies of exon1 of the huntingtin gene that contains a highly pathogenic 120 CAG-repeat expansion. We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6/2 mice at a pre-symptomatic (e.g., embryonic) and symptomatic (e.g., between 3 and 10 weeks postnatal) time points. We identified changes in several signaling cascades, for example, the Akt/FoxO3/CDK2, mTOR/ULK1, and RAF/MEK/CREB pathways. We also identified the Rho-Rac GTPase cascade that contributes to cytoskeleton organization through modulation of the actin-binding proteins, cofilin and profilin. Immunoblotting revealed higher levels of phosphoSer138-profilin in embryonic R6/2 mouse samples (cf. WT mice) that diminish progressively and significantly over the postnatal, symptomatic course of the disease. We detected sex- and genotype-dependent patterns in the phosphorylation of actin-regulators such a ROCK2, PAK, LIMK1, cofilin, and SSH1L, yet none of these aligned consistently with the changing levels of phosphoSer138-profilin. This could be reflecting an imbalance in the sequential influences these regulators are known to exert on actin signaling. The translational potential of these observations was inferred from preliminary observations of changes in LIMK-cofilin signaling and loss of neurite integrity in neural stem cells derived from an HD patient (versus a healthy control). Our observations suggest that a pre-symptomatic, neurodevelopmental onset of change in the phosphorylation of Ser138-profilin, potentially downstream of distinct signaling changes in male and female mice, could be contributing to cytoskeletal phenotypes in the R6/2 mouse model of HD pathology.

亨廷顿病 (HD) 的 R6/2 转基因小鼠模型携带亨廷顿蛋白外显子 1 的多个拷贝含有高致病性 120 个 CAG 重复扩增的基因。我们使用激酶组分析来筛选来自野生型 (WT) 和 R6/2 小鼠在症状前（例如，胚胎）和症状（例如，出生后 3 至 10 周）时间点的神经组织中的激酶活性模式。我们发现了几个信号级联的变化，例如 Akt/FoxO3/CDK2、mTOR/ULK1 和 RAF/MEK/CREB ​​通路。我们还确定了通过调节肌动蛋白结合蛋白、cofilin 和 profilin 促进细胞骨架组织的 Rho-Rac GTPase 级联反应。免疫印迹显示胚胎 R6/2 小鼠样品（参见 WT 小鼠）中更高水平的 phosphoSer138-profilin，在疾病的产后症状过程中逐渐显着减少。我们检测到 ROCK2、PAK、LIMK1、cofilin 和 SSH1L 等肌动蛋白调节因子磷酸化的性别和基因型依赖性模式，但这些模式都没有与 phosphoSer138-profilin 水平的变化一致。这可能反映了已知这些调节剂对肌动蛋白信号施加的顺序影响的不平衡。这些观察结果的转化潜力是从来自 HD 患者（相对于健康对照）的神经干细胞中 LIMK-cofilin 信号传导变化和神经突完整性丧失的初步观察推断出来的。我们的观察表明，Ser138-profilin 磷酸化的症状前、神经发育开始发生变化，可能是雄性和雌性小鼠不同信号变化的下游，