Changes in neurodegeneration-related miRNAs in brains from CAPN1 mice.

Calpain-1 knock-out (KO) mice exhibit enhanced susceptibility to neurodegeneration due to the lack of the neuroprotective function of calpain-1. Dicer has been shown to play a fundamental role in the biogenesis of most miRNAs. Here, we identified 45 differentially expressed miRNAs (DE miRNAs) in the brain of calpain-1 KO mice, as compared to wild-type mice. In particular, among all the DE miRNAs, 7 neurodegeneration-related miRNAs were found to be down-regulated in calpain-1 KO mice. We also found that Dicer is cleaved by calpain-1 in mouse brain, which generates an active fragment of Dicer with RNAse III activity and increases miRNA formation. Levels of active Dicer were reduced in brain homogenates from calpain-1 KO mice and incubation with calpain-1 and calcium restored Dicer activity and miRNA expression. Our results indicate that calpain-1 deletion results in decreased levels of active Dicer and changes in neurodegenerative-related miRNAs. These findings could account for some of the pathological changes found in brain of various mammals, including humans, with calpain-1 mutations or down-regulation.