Astrocytic YAP prevents the demyelination through promoting expression of cholesterol synthesis genes in experimental autoimmune encephalomyelitis

Jingjing Zhang,Xu Zhang,Haoyu Qiu,Changnan Xie,Wenjin Feng,Mianxian Wang,Ying Wang,Jiaojiao Wang,Xiya Shen,Lihao Wu,Weiwei Xiang,Xingxing Xu,Zhihui Huang,Huitao Liu,Danlu Yang,Tianyingying Dong,Lingting Jin

doi:10.1038/s41419-021-04203-8

Abstract

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.

Highlights

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized by inflammation, demyelination and dyskinesia, the etiology remains elusive [1, 2]
YAP is upregulated and activated in astrocytes of EAE mice dependent on suppression of the Hippo pathway including MST1, SAV1, LATS1, and MOB1, and promotes the proliferation of astrocytes and induces the expression of cholesterol-synthesis genes such as HMG-CoA synthase 1 (HMGCS1), which contributes to preventing the demyelination in the spinal cords of EAE mice
Recent reports have shown that YAP is upregulated and activated in astrocytes through suppression of the Hippo pathway after spinal cord injury, and promotes glial scar formation and neural regeneration, and improves functional recovery of mice after SCI [41]

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized by inflammation, demyelination and dyskinesia, the etiology remains elusive [1, 2]. Astrocytes, one of the most abundant cell types in the CNS that exert multiple functions, have generally been considered as a secondary player in EAE, and received less attention [7, 12,13,14,15]. Astrocytes are activated within demyelinating lesions, contribute to astrocytic scar formation, regulate demyelination and remyelination of the axons and play dual roles in neuroinflammation of MS and EAE [13, 15, 18,19,20,21,22] It remains unclear how astrocytes regulate the neuroinflammation and demyelination during EAE. In the CNS, regeneration of myelin is mediated by Received: 28 April 2021 Revised: 13 September 2021 Accepted: 22 September 2021

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