Abstract
Calpains represent a family of calcium-dependent proteases participating in a multitude of functions under physiological or pathological conditions. Calpain-1 is one of the most studied members of the family, is ubiquitously distributed in organs and tissues, and has been shown to be involved in synaptic plasticity and neuroprotection in mammalian brain. Calpain-1 deletion results in a number of phenotypic alterations. While some of these alterations can be explained by the acute functions of calpain-1, the present study was directed at studying alterations in gene expression that could also account for these phenotypic modifications. RNA-seq analysis identified 354 differentially expressed genes (DEGs) in brain of calpain-1 knock-out mice, as compared to their wild-type strain. Most DEGs were classified in 10 KEGG pathways, with the highest representations in Protein Processing in Endoplasmic Reticulum, MAP kinase and Alzheimer’s disease pathways. Most DEGs were down-regulated and validation of a number of these genes indicated a corresponding decreased expression of their encoded proteins. The results indicate that calpain-1 is involved in the regulation of a significant number of genes affecting multiple brain functions. They also indicate that mutations in calpain-1 are likely to be involved in a number of brain disorders.
Highlights
Calpains represent a family of calcium-dependent proteases, which participate in the regulation of a variety of functions under physiological and pathological conditions
While we have identified a number of calpain-1 targets that could be involved in some of the functions regulated by calpain-1, including PHLPP1, SCOP, and RhoA (Wang et al, 2013; Briz et al, 2015), it is likely that changes in transcription could be involved in the phenotypic alterations observed in calpain-1 KO mice
Our results indicate that calpain-1 regulates a much wider set of genes in brain than in muscle, and that these genes belong to signaling pathways involved among others in protein quality control and Alzheimer’s disease
Summary
Calpains represent a family of calcium-dependent proteases, which participate in the regulation of a variety of functions under physiological and pathological conditions. Calpain-1 KO mice are impaired in theta burst stimulation- (TBS) induced long-term potentiation (LTP) of synaptic transmission in hippocampus and in various forms of learning and memory (Liu et al, 2016; Heysieattalab et al, 2019) They exhibit a mild form of cerebellar ataxia resulting from the immaturity of the synaptic contacts between the parallel fibers and the Purkinje neurons in cerebellum (Wang et al, 2016a). Similar results were found in the Russel terrier dogs (Forman et al, 2013) and in humans with null mutations in the calpain-1 gene (GanOr et al, 2016) These mice are more susceptible to neuronal damage in mouse models of acute glaucoma and traumatic brain injury, indicating that calpain-1 has an additional neuroprotective function (Wang et al, 2016b, 2018)
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