Astrocytic YAP prevents the demyelination through promoting expression of cholesterol synthesis genes in experimental autoimmune encephalomyelitis.
Astrocytic YAP prevents the demyelination through promoting expression of cholesterol synthesis genes in experimental autoimmune encephalomyelitis.
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DOI：
10.1038/s41419-021-04203-8
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发表时间：
2021-10-05
影响因子：
9
通讯作者：
Huang Z
中科院分区：
文献类型：
--
作者：
Zhang J;Xu X;Liu H;Jin L;Shen X;Xie C;Xiang W;Yang D;Feng W;Wang J;Wang M;Dong T;Qiu H;Wu L;Wang Y;Zhang X;Huang Z
胆固醇是髓鞘的主要成分，主要由星形胶质细胞合成，并运输到成人大脑中的少突胶质细胞和神经元。已有报道河马/YAP信号通路参与肝脏胆固醇合成，然而，YAP信号是否能通过促进实验性自身免疫性脑脊髓炎(EAE)的胆固醇合成来防止脱髓鞘尚不清楚，EAE是一种以神经炎症和脱髓鞘为特征的多发性硬化症动物模型。在这里，我们发现YAP在EAE小鼠脊髓星形胶质细胞中上调并激活，这是通过抑制河马途径实现的。星形胶质细胞中的YAP缺失加重了EAE的发病时间，炎性细胞浸润更严重，脱髓鞘和更多的神经元丢失。此外，我们还发现YAPGFAP-CKO EAE小鼠的神经炎症加重，星形胶质细胞增殖减少。机制方面，RNAseq显示YAP−/−星形胶质细胞中胆固醇合成途径基因如HMGCS1的表达减少。定量聚合酶链式反应、免疫印迹和免疫染色进一步证实了YAPGFAP-CKO EAE小鼠脊髓星形胶质细胞HMGCS1的表达明显减少。有趣的是，二芳基丙腈(一种ERβ配体，以上调HMGCS1的表达)上调胆固醇合成途径的治疗部分挽救了YAPGFAP-CKO EAE小鼠的脱髓鞘缺陷。最后，XMU-MP-1治疗激活YAP可促进星形胶质细胞HMGCS1的表达，并部分挽救EAE小鼠脱髓鞘和炎性浸润缺陷。这些发现证实了星形细胞YAP通过促进EAE的胆固醇合成来防止脱髓鞘的未知功能，并揭示了YAP/HMGCS1在EAE病理中参与胆固醇合成的新途径。
Cholesterols are the main components of myelin, and are mainly synthesized in astrocytes and transported to oligodendrocytes and neurons in the adult brain. It has been reported that Hippo/yes-associated protein (YAP) pathways are involved in cholesterol synthesis in the liver, however, it remains unknown whether YAP signaling can prevent the demyelination through promoting cholesterol synthesis in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis characterized by neuroinflammation and demyelination. Here, we found that YAP was upregulated and activated in astrocytes of spinal cords of EAE mice through suppression of the Hippo pathway. YAP deletion in astrocytes aggravated EAE with earlier onset, severer inflammatory infiltration, demyelination, and more loss of neurons. Furthermore, we found that the neuroinflammation was aggravated and the proliferation of astrocytes was decreased in YAPGFAP-CKO EAE mice. Mechanically, RNA-seq revealed that the expression of cholesterol-synthesis pathway genes such as HMGCS1 were decreased in YAP−/− astrocytes. qPCR, western blot, and immunostaining further confirmed the more significant reduction of HMGCS1 in spinal cord astrocytes of YAPGFAP-CKO EAE mice. Interestingly, upregulation of cholesterol-synthesis pathways by diarylpropionitrile (DPN) (an ERβ-ligand, to upregulate the expression of HMGCS1) treatment partially rescued the demyelination deficits in YAPGFAP-CKO EAE mice. Finally, activation of YAP by XMU-MP-1 treatment promoted the expression of HMGCS1 in astrocytes and partially rescued the demyelination and inflammatory infiltration deficits in EAE mice. These findings identify unrecognized functions of astrocytic YAP in the prevention of demyelination through promoting cholesterol synthesis in EAE, and reveal a novel pathway of YAP/HMGCS1 for cholesterol synthesis in EAE pathology.
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影响因子：
5.3
作者：
Li, Yijian;Huo, Shujia;Xu, Haiwei
通讯作者：
Xu, Haiwei
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
星形胶质细胞在多发性硬化症进展中的作用。
影响因子：
3.4
作者：
Correale J;Farez MF
通讯作者：
Farez MF
影响因子：
64.8
作者：
Hubler Z;Allimuthu D;Bederman I;Elitt MS;Madhavan M;Allan KC;Shick HE;Garrison E;T Karl M;Factor DC;Nevin ZS;Sax JL;Thompson MA;Fedorov Y;Jin J;Wilson WK;Giera M;Bracher F;Miller RH;Tesar PJ;Adams DJ
通讯作者：
Adams DJ
Neogenin 促进 BMP2 激活 YAP 和 Smad1，并增强发育中的小鼠新皮质的星形胶质细胞分化
影响因子：
5.3
作者：
Huang, Zhihui;Sun, Dong;Xiong, Wen-Cheng
通讯作者：
Xiong, Wen-Cheng