The demonstration of neuronal lysosomal disruption in sCJD made us speculate that release of lysosomal content, especially Cathepsins, could be a key determinant on the neurotoxicity linked to prion diseases through the so-called Calpain-Cathepsin hypothesis observed in some neurological and neurodegenerative conditions [88, 103]. The gene discussed is CTSS; the disease is prion disease.