Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Figure 2

Calpain targets in the autophagic machinery. Calpains can impair protein clearance on different levels of the ALP. By cleaving signal transduction molecules, like , or autophagic proteins, like beclin-1 and ATG5, calpains lead to a reduction of autophagy initiation and can, in the case of ATG5 cleavage, act as a switch from autophagy to apoptosis. Moreover, the cleavage of adapter proteins (optineurin, p62/SQSTM1), cargo (e.g., disease proteins), or lysosome-associated proteins (LAMPs) can change the dynamics of cargo degradation, thereby causing a defect in protein homeostasis. The inhibitory function of CAST reduces calpain activity and thereby leads to increased autophagy levels. Additionally, it prevents the cleavage of disease proteins into toxic or strongly aggregating fragments, rendering more soluble, full-length forms of the protein more accessible to autophagy.