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Astrocytic YAP prevents the demyelination through promoting expression of cholesterol synthesis genes in experimental autoimmune encephalomyelitis.
- Source :
-
Cell death & disease [Cell Death Dis] 2021 Oct 05; Vol. 12 (10), pp. 907. Date of Electronic Publication: 2021 Oct 05. - Publication Year :
- 2021
-
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 YAP <superscript>GFAP</superscript> -CKO EAE mice. Mechanically, RNA-seq revealed that the expression of cholesterol-synthesis pathway genes such as HMGCS1 were decreased in YAP <superscript>-/-</superscript> astrocytes. qPCR, western blot, and immunostaining further confirmed the more significant reduction of HMGCS1 in spinal cord astrocytes of YAP <superscript>GFAP</superscript> -CKO EAE mice. Interestingly, upregulation of cholesterol-synthesis pathways by diarylpropionitrile (DPN) (an ERĪ²-ligand, to upregulate the expression of HMGCS1) treatment partially rescued the demyelination deficits in YAP <superscript>GFAP</superscript> -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.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Astrocytes pathology
Body Weight
Cell Proliferation
Down-Regulation genetics
Encephalomyelitis, Autoimmune, Experimental pathology
Encephalomyelitis, Autoimmune, Experimental physiopathology
Hippo Signaling Pathway
Inflammation pathology
Mice, Knockout
Models, Biological
Neurons metabolism
Neurons pathology
RNA, Messenger genetics
RNA, Messenger metabolism
Recovery of Function
Spinal Cord pathology
Spinal Cord ultrastructure
Up-Regulation genetics
YAP-Signaling Proteins deficiency
YAP-Signaling Proteins metabolism
Mice
Astrocytes metabolism
Cholesterol biosynthesis
Demyelinating Diseases genetics
Encephalomyelitis, Autoimmune, Experimental genetics
Gene Expression Regulation
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 12
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 34611127
- Full Text :
- https://doi.org/10.1038/s41419-021-04203-8