USP9X-mediated deubiquitination of Raptor contributes to autophagy impairment and memory deficits in P301S mice.

Autor: Zheng S; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Zhu J; Department of Neurology, Wuhan Fourth Hospital, Wuhan, 430033, China., Wang C; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Wu Y; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Sun S; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Guo H; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Chang Y; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China., Ma R; Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. marong1109@163.com., Li G; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. gangli2008@hust.edu.cn.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Oct 24; Vol. 22 (1), pp. 516. Date of Electronic Publication: 2024 Oct 24.
DOI: 10.1186/s12964-024-01872-8
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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