The Calcium-Dependent Protease Calpain in Neuronal Remodeling and Neurodegeneration

Abstract

Calpains are evolutionarily conserved and widely expressed Ca 2+ -activated cysteine proteases that act at neutral pH. The activity of calpains is tightly regulated, given that their abnormal activation can have deleterious effects leading to promiscuous cleavage of various targets. Genetic mutations in the genes encoding calpains are associated with human diseases, while abnormally elevated Ca 2+ levels promote Ca 2+ -dependent calpain activation in pathologies associated with ischemic insults and neurodegeneration. In this review, we discuss recent findings on the regulation of calpain activity and activation as revealed through pharmacological, genetic, and optogenetic approaches. Furthermore, we highlight studies elucidating the role of calpains in dendrite pruning and axon degeneration in the context of Ca 2+ homeostasis. Finally, we discuss future directions for the study of calpains and potential therapeutic strategies for inhibiting calpain activity in neurodegenerative diseases.