Lopez Ana, Siddiqi Farah H, Villeneuve Julien, Ureshino Rodrigo Portes, Jeon Hee-Yeon, Koulousakis Philippos, Keeling Sophie, McEwan William A, Fleming Angeleen, Rubinsztein David C
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Nat Chem Biol. 2025 Apr;21(4):577-587. doi: 10.1038/s41589-024-01762-7. Epub 2024 Oct 31.
Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick's disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer's disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.
tau蛋白病是一类神经退行性疾病，其特征为tau蛋白在细胞内积聚和聚集。这些疾病包括皮克病、进行性核上性麻痹、皮质基底节变性和嗜银颗粒病，其中tau蛋白被认为是主要的致病因素，还包括继发性tau蛋白病，如阿尔茨海默病。因此，需要开发有效的药物治疗方法。在此，我们使用转基因斑马鱼tau蛋白病模型对1400多种临床批准的化合物进行了测试。结果显示，碳酸酐酶（CA）抑制剂可预防tau蛋白毒性。CRISPR实验证实，CA缺失模拟了这些药物的作用。CA抑制通过促进溶酶体胞吐作用，加速了人tau蛋白的清除。重要的是，临床使用的CA抑制剂甲醋唑胺，在与人体相似的浓度下，也降低了小鼠tau蛋白病模型中总tau蛋白和磷酸化tau蛋白水平，提高了神经元存活率，并改善了神经退行性变。这些数据强调了使用斑马鱼模型进行体内药物筛选的可行性，并建议认真考虑将CA抑制剂用于治疗tau蛋白病。
