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.