Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin (HTT) [55]. While the final pathological consequence of HD is the neuronal cell death in the striatum region of the brain, it is still unclear how mutant HTT (mHTT) causes synaptic dysfunctions at the early stage and during the progression of HD. Here, we discovered that the basal activity of focal adhesion kinase (FAK) is severely reduced in a striatal HD cell line, a mouse model of HD, and the human post-mortem brains of HD patients. In addition, we observed with a FRET-based FAK biosensor [59] that neurotransmitter-induced FAK activation is decreased in HD striatal neurons. Total internal reflection fluorescence (TIRF) imaging revealed that the reduced FAK activity causes the impairment of focal adhesion (FA) dynamics, which further leads to the defect in filopodial dynamics causing the abnormally increased number of immature neurites in HD striatal neurons. Therefore, our results suggest that the decreased FAK and FA dynamics in HD impair the proper formation of neurites, which is crucial for normal synaptic functions [52]. We further investigated the molecular mechanism of FAK inhibition in HD and surprisingly discovered that mHTT strongly associates with phosphatidylinositol 4,5-biphosphate, altering its normal distribution at the plasma membrane, which is crucial for FAK activation [14, 60]. Therefore, our results provide a novel molecular mechanism of FAK inhibition in HD along with its pathological mechanism for synaptic dysfunctions during the progression of HD.

亨廷顿病（HD）是一种由亨廷顿蛋白（HTT）中聚谷氨酰胺扩增引起的神经退行性疾病[55]。虽然HD的最终病理结果是大脑纹状体区域的神经细胞死亡，但突变型HTT（mHTT）如何在HD早期和进展过程中导致突触功能障碍仍不清楚。在这里，我们发现纹状体 HD 细胞系、HD 小鼠模型和 HD 患者死后大脑中粘着斑激酶 (FAK) 的基础活性严重降低。此外，我们使用基于 FRET 的 FAK 生物传感器观察到，HD 纹状体神经元中神经递质诱导的 FAK 激活减少。全内反射荧光（TIRF）成像显示，FAK活性降低导致粘着斑（FA）动力学受损，进一步导致丝状伪足动力学缺陷，导致HD纹状体神经元中未成熟神经突数量异常增加。因此，我们的结果表明，HD 中 FAK 和 FA 动力学的降低会损害神经突的正常形成，而神经突的形成对于正常突触功能至关重要 [52]。我们进一步研究了 HD 中 FAK 抑制的分子机制，并令人惊讶地发现 mHTT 与磷脂酰肌醇 4,5-二磷酸强烈相关，改变其在质膜上的正常分布，这对于 FAK 激活至关重要 [14, 60]。因此，我们的研究结果提供了 HD 中 FAK 抑制的新分子机制，以及 HD 进展过程中突触功能障碍的病理机制。