Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis.

Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long-term neurological disabilities that are not amenable to current immunomodulatory therapies. Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)-induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury-response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.