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Abstract
BACKGROUND: Loss-of-function mutations in the gene encoding cystatin B (CSTB) underlie an inherited neurodegenerative disorder, progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). CSTB is an inhibitor of several papain-family cysteine proteases, the lysosomal cathepsins. Its physiological function and the molecular pathways leading to the clinical EPM1 phenotype are unknown. AIM: To elucidate the role of CSTB and different cathepsins in pathogenesis of EPM1. METHOD: We determined the total papain inhibitory (cystatin) and papain-like (cathepsin) activity as well as specific activities of cathepsins B, H, L and S in lymphoblastoid cells of EPM1 patients, carriers and controls. RESULTS: In EPM1 patients, who express reduced levels of CSTB mRNA, the papain inhibitory activity was significantly decreased or absent. This reduction was correlated with significant increase in general cathepsin activity. The increase in cathepsin B, L and S activities was highly significant, whereas the increase in cathepsin H activity was not. CONCLUSIONS: This is the first demonstration of cysteine protease activity being regulated by CSTB activity in a biological context. The effects of decreased CSTB activity in EPM1 pathogenesis may, at least in part, be mediated by cathepsins through increased activity of cathepsins S and L.
