PR002769 (Project)

Description:Progressive multiple sclerosis (PMS) is characterized by neurodegeneration independent of clinical relapses, with senescent glia prominent in chronic lesions. We identified immature, senescent, proinflammatory radial glia-like cells (DARGs) in the PMS brain as key contributors to disease pathobiology. Although cellular senescence and neuroinflammation are recognized as critical contributors, the underlying mechanisms coordinating these processes remain poorly understood. Employing a patient-derived stem cell model that allows precise investigation of the DARG biology, we demonstrate that mitochondria-derived double-stranded RNA ([mt-(ds)RNA)] leaks into the cytosol through VDAC channels, activating antiviral responses via TBK1-IRF3 signalling and promoting cellular senescence. This, in turn, induces reactive astrocytic phenotypes through paracrine mechanisms. Importantly, inhibition of the RIG-I/MDA5-MAVS pathway reverses senescence, reduces inflammation, and restores cellular function. Our findings position cytosolic mt-(ds)RNA sensing as a central mediator of chronic smouldering neuroinflammation in PMS and highlight its potential as a therapeutic target to interrupt ongoing neurodegenerative cascades.