Role of Calpain-1 in Neurogenesis

Abstract

While calpains have been implicated in neurogenesis for a long time, there is still little information regarding the specific contributions of various isoforms in this process. We took advantage of the availability of mutant mice with complete deletion of calpain-1 to analyze its contribution to neurogenesis. We first used the incorporation of BrdU in newly-generated cells in the subgranular zone of the dentate gyrus to determine the role of calpain-1 deletion in neuronal proliferation. Our results showed that the lack of calpain-1 decreased the rate of cell proliferation in adult hippocampus. As previously shown, it also decreased the long-term survival of newly-generated neurons. We also used data from previously reported RNA and miRNA sequencing analyses to identify differentially expressed genes in brain of calpain-1 knock-out mice related to cell division, cell migration, cell proliferation and cell survival. A number of differentially expressed genes were identified, which could play a significant role in the changes in neurogenesis in calpain-1 knock out mice. The results provide new information regarding the role of calpain-1 in neurogenesis and have implications for better understanding the pathologies associated with calpain-1 mutations in humans.

Phosphorylation of Calpastatin Negatively Regulates the Activity of Calpain

“…Calpain also degraded calpastatin, leading to the breakdown of intracellular structures. In medicine, calpain regulates important cellular processes through selective and limited target cell cleavage after the increase of Ca 2+ [ 24 ]. However, under conditions of sustained Ca 2+ increase, calpain proteolysis becomes excessive and its targets undergo extensive degradation.…”

“…The L domain is involved in tight binding to the active site of calpain [ 42 ]. PKA can catalyze the phosphorylation of the L domain of calpastatin, thereby affecting the ability and specificity of calpastatin to inhibit calpain activity [ 24 ]. In the development of drugs, it has been found that the N-terminal regulatory domain of calpastatin undergoes selective splicing compared to the conserved and repetitive four inhibitory domains.…”

“…Amino acid residues corresponding to the haplotype closely related to tenderness in the calpastatin gene can be phosphorylated by protein kinase [ 23 ]. Phosphorylated calpastatin affected its inhibitory efficiency in cells [ 24 ]. Phosphorylation of calpastatin was involved in regulating the stability of the calpain-calpastatin system [ 25 ].…”

Calpain signaling: from biology to therapeutic opportunities in neurodegenerative disorders

“…During neuronal development, calpains participate in various processes such as neurite outgrowth, axon guidance, synaptogenesis, and dendritic spine formation. Calpain-mediated proteolysis is required for the dynamic rearrangement of the cytoskeleton, which is essential for neurite extension and growth cone guidance ( 39 ). By cleaving cytoskeletal proteins, calpains modulate the stability and plasticity of neuronal structures.…”

Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity

“…More specifically, they remove distinct motifs and domains from their target proteins, thereby modulating their structure, function, and activity (Sorimachi et al, 2011 ; Ono et al, 2016 ). They participate in a variety of vital cellular processes, including cell cycle and proliferation, apoptosis, cell motility, signal transduction pathways (Goll et al, 2003 ), neurogenesis (Baudry et al, 2021 ), and synaptic plasticity (Baudry and Bi, 2016 ). Based on their wide spectrum of cellular functions, disruption, and dysregulation of calpains are associated with various diseases (Ono et al, 2016 ).…”