Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies

TL;DR

Sorafenib, a drug already approved for other uses, may help treat tau-related brain diseases like Alzheimer's by reducing harmful tau proteins through multiple mechanisms.

Contribution

This study reveals that sorafenib reduces tau pathology by promoting FBXW7-mediated ubiquitin-proteasome degradation and inhibiting tau phosphorylation.

Findings

Sorafenib reduces total and phosphorylated tau levels in tauopathy model mice.

Sorafenib promotes FBXW7 expression, which binds and degrades tau via the ubiquitin–proteasome pathway.

FBXW7 overexpression in the hippocampus ameliorates cognitive deficits and tau pathologies in PS19 mice.

Abstract

Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin–proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.

Sorafenib mitigates tauopathy via multiple pathways: sorafenib inhibits various kinases to reduce tau phosphorylation, enhances autophagy-mediated tau degradation, and upregulates FBXW7 to promote the ubiquitin-proteasome degradation of ptau231.Image 1

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