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To investigate the neurodegenerative component of MS pathogenesis, we examined the expression of alpha-synuclein, a protein whose accumulation is common to many neurodegenerative disorders, under conditions of immune-mediated inflammatory demyelination. alpha-Synuclein expression was examined in the spinal cord of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats using immunofluorescence and in situ hybridization and in postmortem tissues from cases of secondary progressive MS using immunohistochemistry. alpha-Synuclein upregulation was detected in neurons and glia in and close by lesions and in normal appearing spinal cord EAE tissue at the protein and mRNA levels. alpha-Synuclein positive neurons and glia appeared early, and their number was maximal during EAE exacerbations, but some expression was maintained throughout the course of EAE.]. 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