Zheng Naizhen, Wang Zijie, Cao Jing, Li Kun, Xu Hui, Wang Jinghui, Zhang Lingliang, Meng Jian, Tang Ziqian, Luo Hong, Sun Hao, Zhang Xian, Zhang Yun-Wu
Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
Alzheimers Dement. 2025 Jun;21(6):e70369. doi: 10.1002/alz.70369.
Tauopathy is characterized by the pathology of tau deposits in the brain. Transmembrane protein 59 (TMEM59) is correlated with Alzheimer's disease (AD), the most common type of tauopathy. However, whether and how TMEM59 regulates tau pathology remains unknown.
We analyzed TMEM59 levels in the brains of AD patients and the tau transgenic (PS19) mice, evaluated behaviors and tauopathy-related pathologies in PS19 mice with TMEM59 haploinsufficiency, and studied the regulation of TMEM59 on chaperone-mediated autophagy (CMA) using biochemical analysis.
TMEM59 levels increased in the brains of AD patients and PS19 mice at pathological stages. TMEM59 haploinsufficiency attenuated cognitive deficits and disease-related pathologies in PS19 mice. TMEM59 deficiency promoted lysosome-associated membrane protein type 2A levels and CMA activity, whereas TMEM59 overexpression had the opposite effects.
Our study identifies an important role of TMEM59 in regulating CMA and reveals the potential of targeting TMEM59 for tauopathy intervention.
Transmembrane protein 59 (TMEM59) levels increase in the brains of Alzheimer's disease patients and the tau transgenic (PS19) tauopathy model mice at pathological stages. TMEM59 haploinsufficiency attenuates cognitive deficits, neurodegeneration, synapse dysfunction, gliosis, neuroinflammation, and tau pathology in PS19 mice. TMEM59 interacts with lysosome-associated membrane protein type 2A and heat-shock cognate 71 kDa and regulates chaperone-mediated autophagy. TMEM59 may serve as a therapeutic target for tauopathy.
tau蛋白病的特征是大脑中tau蛋白沉积的病理学变化。跨膜蛋白59（TMEM59）与最常见的tau蛋白病类型——阿尔茨海默病（AD）相关。然而，TMEM59是否以及如何调节tau蛋白病理学仍不清楚。
我们分析了AD患者和tau转基因（PS19）小鼠大脑中的TMEM59水平，评估了TMEM59单倍体不足的PS19小鼠的行为和tau蛋白病相关病理学，并使用生化分析研究了TMEM59对伴侣介导的自噬（CMA）的调节作用。
在病理阶段，AD患者和PS19小鼠大脑中的TMEM59水平升高。TMEM59单倍体不足减轻了PS19小鼠的认知缺陷和疾病相关病理学变化。TMEM59缺乏促进了溶酶体相关膜蛋白2A型水平和CMA活性，而TMEM59过表达则产生相反的效果。
我们的研究确定了TMEM59在调节CMA中的重要作用，并揭示了靶向TMEM59进行tau蛋白病干预的潜力。
在病理阶段，阿尔茨海默病患者和tau转基因（PS19）tau蛋白病模型小鼠大脑中的跨膜蛋白59（TMEM59）水平升高。TMEM59单倍体不足减轻了PS19小鼠的认知缺陷、神经退行性变、突触功能障碍、胶质增生、神经炎症和tau蛋白病理学变化。TMEM59与溶酶体相关膜蛋白2A型和热休克同源71 kDa相互作用并调节伴侣介导的自噬。TMEM59可能成为tau蛋白病的治疗靶点。
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