“…One of the most controversial issues regarding the role of lysosomal proteases outside the lysosomes is their actual ability to function at neutral pH. A series of elegant studies showed that, although lysosomal enzymes have an activity optimum at acidic pH, lysosomal cysteine proteases are stable and active at neutral pH for a time that ranges from a few minutes to an hour or more, confirming their destructive potential in cellular compartments other than the lysosomes (Turk et al, 1993(Turk et al, , 1995(Turk et al, , 2000. Cathepsin B, which is one of the most stable proteases at physiologic pH, is essential in different models of apoptosis, including bile acid-induced hepatocyte apoptosis (Roberts et al, 1997;Jones et al, 1998;Faubion et al, 1999;Canbay et al, 2003), TNF-ainduced apoptosis of primary hepatocytes and tumor cells (Guicciardi et al, 2000(Guicciardi et al, , 2001Foghsgaard et al, 2001), neuronal apoptosis in Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) (Houseweart et al, 2003a) and after brain ischemia (Yamashima et al, 1998;Tsuchiya et al, 1999), and PC12 cell apoptosis after serum deprivation (Shibata et al, 1998).…”