TMEM59 deficiency activates chaperone-mediated autophagy and ameliorates disease-like pathologies in tauopathy model mice

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-06-23 DOI:10.1002/alz.70369

Naizhen Zheng, Zijie Wang, Jing Cao, Kun Li, Hui Xu, Jinghui Wang, Lingliang Zhang, Jian Meng, Ziqian Tang, Hong Luo, Hao Sun, Xian Zhang, Yun-wu Zhang

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Abstract

INTRODUCTION

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.

METHODS

We analyzed TMEM59 levels in the brains of AD patients and the tau^P301S 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.

RESULTS

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.

DISCUSSION

Our study identifies an important role of TMEM59 in regulating CMA and reveals the potential of targeting TMEM59 for tauopathy intervention.

Highlights

Transmembrane protein 59 (TMEM59) levels increase in the brains of Alzheimer's disease patients and the tau^P301S 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.

Abstract Image

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TMEM59缺陷激活伴侣介导的自噬并改善牛头病模型小鼠的疾病样病理

tau病以脑内tau沉积的病理为特征。跨膜蛋白59 （TMEM59）与阿尔茨海默病（AD）相关，AD是最常见的牛头病类型。然而，TMEM59是否以及如何调节tau病理仍然未知。方法分析AD患者和tauP301S转基因（PS19）小鼠大脑中TMEM59水平，评价TMEM59单倍不全PS19小鼠的行为和tau病相关病理，并通过生化分析研究TMEM59对伴侣介导的自噬（CMA）的调控作用。结果AD患者和PS19小鼠在病理阶段脑组织中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。TMEM59缺乏促进溶酶体相关膜蛋白2A水平和CMA活性，而TMEM59过表达则具有相反的作用。我们的研究确定了TMEM59在调节CMA中的重要作用，并揭示了针对TMEM59进行牛头病干预的潜力。跨膜蛋白59 （TMEM59）水平在阿尔茨海默病患者和tauP301S转基因（PS19）脑损伤模型小鼠的病理阶段升高。TMEM59单倍不全可减轻PS19小鼠的认知缺陷、神经退行性变、突触功能障碍、胶质瘤、神经炎症和tau病理。TMEM59与溶酶体相关膜蛋白2A型和热休克同源蛋白71 kDa相互作用，调节伴侣介导的自噬。TMEM59可能作为tau病的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.