Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

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.

Role of Calpain-1 in Neurogenesis

“…Interestingly, one of the genes significantly down-regulated in the brains of C1KO mice is Nr4a1, which we previously validated in our RNA-Seq analysis by RT-qPCR and showed that the protein was also down-regulated in hippocampus. Nr4a1 is involved in many functions including apoptosis, and we found that it colocalized with doublecortin in the dentate gyrus and was present in newly-born neurons (Su et al, 2020). Nr4a3 has also been previously identified as playing a role in hippocampal neurogenesis (Ashbrook et al, 2014) and is significantly downregulated in brains of C1KO mice.…”

“…We recently performed RNA-Seq analysis to compare gene expression in brains of WT and C1KO mice ( Su et al, 2020 ). We reanalyzed the data to identify which genes related to neurogenesis were differentially expressed in brains of these mice ( Supplementary Table S1 ).…”

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes

“…CAPN1 (OMIM # 114220) encodes calpain-1, a large subunit of μ-calpain, a calcium-activated cysteine protease widely present in the central nervous system. Mutations in CAPN1 have been linked to hereditary spastic paraplegia type 76, which is characterized by adult-onset, chronically progressive corticospinal tract dysfunction (SPG76) with variable cerebellar dysfunction, peripheral neuropathy, and urinary symptoms including incontinence [ 23 – 25 ]. At the most recent follow-up, the patient has not manifested any signs of pyramidal tract dysfunction (spasticity, hyperreflexia, abnormal plantar response), cerebellar dysfunction/ataxia, or peripheral neuropathy, although we cannot exclude that these may later develop with age.…”

Hereditary Spastic Paraplegia: An Update

“…Calpain 1 (CAPN1) at 11q13.1 is studied widely due to its universal presence in various tissues and organs, and its predominant role is protecting and maintaining neurons plasticity in the synaptic regions and alterations comprehend to various brain disorders [79].…”