Dysregulation of the endosomal sorting complex III is linked to neurodegeneration in progressive multiple sclerosis.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that progresses to a stage marked by irreversible neurological decline and widespread neurodegeneration. Necroptosis, a regulated form of cell death primarily triggered by tumor necrosis factor (TNF), has been implicated in neuronal loss in progressive MS. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery, essential for plasma membrane repair and vesicle trafficking, is known to counteract necroptosis in non-neural cells. In this study, we investigated whether ESCRT dysfunction contributes to neurodegeneration in the MS cortex. We identified a significant dysregulation of ESCRT-III complex components, particularly VPS4B and CHMP2A, in neurons of MS cortical grey matter. This dysregulation correlated with reduced neuronal density and increased meningeal inflammation. Notably, both demyelinated and normal-appearing grey matter showed decreased VPS4B, while CHMP2A loss was more restricted to areas of demyelination. These findings suggest that impaired ESCRT-III function may increase neuronal vulnerability to necroptosis and contribute to disease progression in MS. Our results highlight a novel pathway linking neuroinflammation, ESCRT dysfunction, and neuronal death, with potential therapeutic implications for neuroprotection in progressive MS.