小柯机器人

美国贝勒医学院Hui Zheng研究组发现，TFEB-液泡ATP酶信号调节tau病理中的溶酶体功能和小胶质细胞活化。相关论文于2023年11月20日在线发表于《自然—神经科学》期刊。

研究人员表示，转录因子 EB（TFEB）通过与协调溶酶体表达和调控（CLEAR）序列结合来介导基因表达。TFEB的靶标包括液泡ATP酶（v-ATP酶）的亚基，这些亚基对溶酶体的酸化至关重要。

研究人员对表达P301S突变体tau的野生型小鼠和PS19（Tau）转基因小鼠进行单核 RNA 测序，在Tau小鼠中发现了三个独特的小胶质细胞亚群，它们与溶酶体和免疫途径基因的增加有关。为了探究溶酶体与免疫之间的关系，研究人员通过创建一个基因敲入小鼠系，使其中一个v-ATP酶亚基Atp6v1h的CLEAR序列发生突变，从而特异性地破坏了TFEB-v-ATP酶信号转导。CLEAR突变体对TFEB的反应不明显，导致溶酶体酸化和活性受损。将CLEAR突变体与Tau小鼠杂交会导致更高的tau病理，但小胶质细胞的反应会减弱。这些小胶质细胞富集在一个mTOR和HIF-1通路较低的亚群中，并锁定在一种平衡状态。这项研究证明了TFEB-v-ATP酶信号在维持溶酶体平衡方面的生理功能，以及溶酶体在启动小胶质细胞和免疫反应以治疗tau病理和阿尔茨海默病中的关键作用。

附：英文原文

Title: TFEB–vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy

Author: Wang, Baiping, Martini-Stoica, Heidi, Qi, Chuangye, Lu, Tzu-Chiao, Wang, Shuo, Xiong, Wen, Qi, Yanyan, Xu, Yin, Sardiello, Marco, Li, Hongjie, Zheng, Hui

Issue&Volume: 2023-11-20

Abstract: Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome–immune relationship, we specifically disrupted the TFEB–v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB–v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer’s disease.

DOI: 10.1038/s41593-023-01494-2

Source: https://www.nature.com/articles/s41593-023-01494-2

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex