Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors
Advanced Science ( IF 14.3 ) Pub Date : 2024-09-12 , DOI: 10.1002/advs.202403389
Jia-Wen Mo ₁ , Peng-Li Kong ₁ , Li Ding ₁ , Jun Fan ₁ , Jing Ren ₁ , Cheng-Lin Lu _{1,

2} , Fang Guo ₁ , Liang-Yu Chen ₁ , Ran Mo ₁ , Qiu-Ling Zhong ₁ , You-Lu Wen ₃ , Ting-Ting Gu ₃ , Qian-Wen Wang ₄ , Shu-Ji Li ₁ , Ting Guo ₁ , Tian-Ming Gao ₁ , Xiong Cao _{1,

2,

5}

Affiliation

Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5′-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

中文翻译：

星形胶质细胞中的溶酶体 TFEB-TRPML1 轴调节抑郁样行为

溶酶体是人类健康的重要细胞结构，是回收、信号传导、新陈代谢和应激适应的中心。然而，溶酶体在压力相关情绪中的潜在作用长期以来一直被忽视。在这里，发现星形胶质细胞的溶酶体形态在慢性社交失败应激后易感小鼠的内侧前额叶皮层（mPFC）中发生改变。溶酶体相关基因的筛选显示，粘脂蛋白 1 基因（Mcoln1;蛋白质：粘脂蛋白 TRP 通道 1）的表达在易感小鼠和抑郁症患者中降低。粘脂蛋白 TRP 通道 1 （TRPML1）的星形胶质细胞特异性敲除通过抑制溶酶体胞吐作用介导的 5′-三磷酸腺苷（ATP）释放诱导抑郁样行为。此外，星形胶质细胞溶酶体的这种应激反应是由转录因子 EB （TFEB）介导的，TRPML1 的过表达挽救了星形胶质细胞特异性敲除 TFEB 诱导的抑郁样行为。总的来说，这些发现揭示了导致抑郁症发展的溶酶体应激感应信号通路，并将溶酶体确定为抗抑郁药的潜在靶细胞器。

更新日期：2024-09-12

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南