2. Academic Validation
  3. 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

  • Cell Death Dis. 2021 Oct 5;12(10):907. doi: 10.1038/s41419-021-04203-8.
Jingjing Zhang  # 1 2,  Xingxing Xu  # 2,  Huitao Liu  # 3,  Lingting Jin 2,  Xiya Shen 2,  Changnan Xie 3,  Weiwei Xiang 4,  Danlu Yang 2,  Wenjin Feng 5,  Jiaojiao Wang 2,  Mianxian Wang 2,  Tianyingying Dong 2,  Haoyu Qiu 2,  Lihao Wu 2,  Ying Wang 6,  Xu Zhang 7,  Zhihui Huang 8 9 10
Affiliations

Affiliations

  • 1 School of Pharmacy, and Department of Neurosurgery of the Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 2 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 Zhejiang Sinogen Medical Equipment Co., Ltd., Wenzhou, Zhejiang, China.
  • 6 Phase I Clinical Research Center, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 7 Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 8 School of Pharmacy, and Department of Neurosurgery of the Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China. [email protected].
  • 9 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 10 Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 34611127 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.

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