Astrocytic TIA1‐Mediated Stress Granules Promote the Demyelination of Optic Neuritis by Sequestering mRNA of Cholesterol Synthesis Genes in an Experimental Autoimmune Encephalomyelitis Model

ABSTRACT Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS), characterized by inflammation and demyelination of the optic nerves. Recent studies indicate increased expression of genes associated with stress granules (SGs) in MS, with T cell intracellular antigen 1 (TIA1) being a key component of SGs. However, the role of TIA1‐mediated SGs in MS‐ON remains unclear. In experimental autoimmune encephalomyelitis (EAE) mice, a model of MS, TIA1 and G3BP1 + (a cell marker of SGs) SGs were upregulated in retinal neurons and optic nerve astrocytes. Knockout of Tia1 in the CNS ( Tia1 Nestin ‐CKO mice) suppressed demyelination, inflammatory infiltration, and retinal ganglion cells (RGCs) loss in EAE mice. Mechanically, RNA‐sequencing analysis revealed upregulation of cholesterol synthesis genes such as hmgcs1 in Tia1 Nestin ‐CKO EAE mice. Furthermore, deletion of Tia1 in astrocytes ( Tia1 GFAP ‐CKO mice) also alleviated demyelination in optic nerves in EAE mice through decreasing SG formation and increasing HMGCS1 expression in Tia1 −/− astrocytes by decreasing the sequestration of hmgcs1 mRNA into SGs. Treatment with diarylpropionitrile (DPN), an ERβ‐ligand, partially restored demyelination in Tia1 GFAP ‐CKO EAE mice. These findings uncover the role of TIA1‐mediated SG dynamics in MS‐ON, highlighting a novel mechanism and potential therapeutic target for treatment.