Fig. 10
Proposed Calpain-Cathepsin S axis activation in sCJD. As a consequence of increased neuronal intracellular Ca2+ concentration in sCJD a broad range of pathologically related events occur such as i) direct or indirect alteration of gene expression patterns and ii) over activation of non-lysosomal cysteine proteases Calpains. On one side, pathological Calpain activity may cleave PrP, enhancing its misfolded conformation and enhancing prion seeding in new conversion cycles. On the other hand, Calpain compromise lysosomal membrane integrity, and as a consequence, Cathepsin proteases are liberated in the cytoplasm. Calpains and proteases with activity at neutral pH, such as Cathepsin S, unspecifically cleave cellular substrates and structures, interfering with physiological cellular functions. When plasma membrane is compromised, the cellular content is released into the extracellular space. Additionally, Cathepsin S expression is overexpressed in microglial cells as a consequence of chronic neuroinflammation