MRI ofCapn15knockout mice and analysis of Capn 15 distribution reveal possible roles in brain development and plasticity

Abstract

The murine Calpain 15 (Capn15) is an intracellular cysteine protease that belongs to the non-classical Small Optic Lobe (SOL) family of calpains. SOL calpains lack the penta-EF-hand structure found in classical calpains, but have N-terminal Zinc Fingers that bind polyubiquitin and a C-terminal SOL domain with poorly characterized function.In this study, we have generated Capn15 transgenic mice and taking advantage of the lacZ reporter under the control of the Capn15 promoter, show that Capn15 is highly expressed in the developing brain and is enriched in the eyes, the superficial cortical layers, the hippocampus, and the Purkinje cells in the cerebellum in the adult. The homozygous loss of Capn15 decreases embryonic survival and weaned mice have smaller brains and weigh less than their WT littermates. MRI studies revealed specific volume losses in the superior parietal cortex and thalamus and in the CA1, CA2, dentate gyrus and stratum granulosum in the hippocampus. Most importantly, Capn15 KO mice had mild to severe eye deficits that ranged from cataracts to microphthalmia (small eye) and anophthalmia (no eye). We further identify a missense homozygous variant of CAPN15 in one patient from a UK cohort with ocular anomalies indicating a potential link between CAPN15 and microphthalmia in humans. Surprisingly, knocking-out the atypical PKC/PKMζ in Capn15 KO mice rescues the severe eye deficits in these mice suggesting that cleavage of PKCζ by Capn15 may play an important role in eye development.

Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

“…Mutations in calpain-5 have recently been associated with autoimmune uveitis and photoreceptor degeneration [22]. Very recent studies have also linked mutations in calpain-15 with various types of developmental eye disorders in humans [23]. Our laboratory has focused mostly on the study of the roles of calpain-1 (aka, µ-calpain) and calpain-2 (aka m-calpain) in the brain [14].…”

Prediction of gene expression from regulatory sequence composition enhances transcriptome-wide association studies

“…CAPN15 was also the top scoring gene for the association with disease status in seven other tissues (hypothalamus, esophagus mucosa, ovary, pancreas, prostate, skin -not sun exposed suprapubic, skin sun exposed lower leg; Figure 2 c). The calpains, to which this gene belongs, are a family of cysteine proteases whose hyperactivation has been previously related to Alzheimer's disease [21]; furthermore, a recent preprint describes how the knockout of CAPN15 in mice impairs brain development and plasticity [22]. Interestingly, CAPN15 has not been previously associated to AD through a GWAS according to the EBI GWAS catalog, showing that our method can find new gene/disease associations.…”