The intriguing “calpain-cathepsin” hypothesis proposed calpain-mediated cleavage of carbonylated Hsp70.1 and led to lysosomal permeabilization and/or rupture with the release of cathepsins, and therefore further deteriorated cytoskeleton stabilization of neurons in neurodegenerative diseases [65]. The gene discussed is CTSS; the disease is neurodegenerative disease.