Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Neurology, Wuhan Fourth Hospital, Wuhan, 430033, China.
Cell Commun Signal. 2024 Oct 24;22(1):516. doi: 10.1186/s12964-024-01872-8.
Tauopathies, including Alzheimer's disease, are characterized by the pathological aggregation of tau protein, which is strongly linked to dysregulation of the autophagy-lysosomal degradation pathway. However, therapeutic strategies targeting this pathway remain limited.
We used both in vitro and in vivo models to investigate the role of Raptor in tau pathology. Knockdown of Raptor was performed to assess its impact on mTORC1 activation, autophagy, and tau accumulation. The relationship between USP9X and Raptor was also examined. Pharmacological inhibition of USP9X with WP1130 was employed to further confirm the involvement of the USP9X-Raptor-mTORC1 axis in tau degradation.
Elevated Raptor levels in the hippocampus of P301S mice led to hyperactivation of mTORC1, impairing autophagy flux. Knockdown of Raptor effectively suppressed mTORC1 activation, promoted autophagy, and mitigated the accumulation of tau and its phosphorylated isoforms. This reduction in tau pathology was accompanied by decreased neuronal loss in the hippocampus, amelioration of synaptic damage, and improvement in cognitive function. The increased Raptor protein observed in the hippocampus of P301S mice was likely attributable to elevated USP9X content, which enhanced Raptor deubiquitination and protected it from proteasomal degradation. Pharmacological inhibition of USP9X with WP1130 in vitro effectively suppressed Raptor, promoted autophagy, and accelerated the degradation of tau and phosphorylated tau.
Our findings highlight Raptor and USP9X as promising molecular targets for therapeutic intervention in tauopathies. Targeting the USP9X-Raptor-mTORC1 axis may provide a novel strategy for promoting autophagy and mitigating tau pathology in Alzheimer's disease and other tauopathies.
包括阿尔茨海默病在内的 Tau 病的特征是 Tau 蛋白的病理性聚集，这与自噬-溶酶体降解途径的失调密切相关。然而，针对该途径的治疗策略仍然有限。
我们使用体外和体内模型来研究 Raptor 在 Tau 病理学中的作用。通过敲低 Raptor 来评估其对 mTORC1 激活、自噬和 Tau 积累的影响。还检查了 USP9X 和 Raptor 之间的关系。使用 WP1130 抑制 USP9X 的药理学抑制作用，进一步证实了 USP9X-Raptor-mTORC1 轴在 Tau 降解中的参与。
P301S 小鼠海马中 Raptor 水平升高导致 mTORC1 过度激活，损害自噬流。敲低 Raptor 可有效抑制 mTORC1 激活，促进自噬，并减轻 Tau 和其磷酸化同工型的积累。Tau 病理学的减少伴随着海马中神经元丢失的减少、突触损伤的改善和认知功能的提高。P301S 小鼠海马中观察到的 Raptor 蛋白增加可能归因于 USP9X 含量的升高，这增强了 Raptor 的去泛素化作用，并防止其被蛋白酶体降解。WP1130 在体外对 USP9X 的药理学抑制作用可有效抑制 Raptor，促进自噬，并加速 Tau 和磷酸化 Tau 的降解。
我们的研究结果强调了 Raptor 和 USP9X 作为 Tau 病治疗干预的有前途的分子靶点。靶向 USP9X-Raptor-mTORC1 轴可能为促进自噬和减轻阿尔茨海默病和其他 Tau 病中的 Tau 病理学提供一种新策略。
