Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations

Abstract

The lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protects β-galactosidase and sialidase Neu1 against proteolytic degradation by forming a multienzyme complex and activates sialidase Neu1. CathA deficiency causes the lysosomal storage disease, galactosialidosis. These patients present with a broad range of clinical phenotypes, including growth retardation, and neurological deterioration along with the accumulation of the vasoactive peptide, endothelin-1, in the brain. Previous in vitro studies have shown that CathA has specific activity against vasoactive peptides and neuropeptides, including endothelin-1 and oxytocin. A mutant mouse with catalytically inactive CathA enzyme (CathAS190A) shows increased levels of endothelin-1. In the present study, we elucidated the involvement of CathA in learning and long-term memory in 3-, 6-, and 12-month-old mice. Hippocampal endothelin-1 and oxytocin accumulated in CathAS190A mice, which showed learning impairments as well as long-term and spatial memory deficits compared with wild-type littermates, suggesting that CathA plays a significant role in learning and in memory consolidation through its regulatory role in vasoactive peptide processing.

Combined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury

“…It also seems to play an important role in autophagy, which is involved in the regulation of various inflammatory mechanisms including SCI [ 69 ]. Recent work in mice showed that CTSA deficiency is associated with a severe neurological phenotype [ 70 ]. Similarly, the role of the other consistently upregulated cathepsins CTSH and CTSZ ( Figure 4 ) in SCI is unknown.…”

Effect of Voluntary Wheel Running on Striatal Dopamine Level and Neurocognitive Behaviors after Molar Loss in Rats

“…Cognitive function was assessed by passive avoidance test [ 28 ]. After the learning trail, the retention test was measured 24 h after the learning trial.…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…The multiple biological functions of CTSA translate into a broad spectrum of clinical manifestations in patients affected by GSL, which are currently classified in three different forms: early infantile, late infantile, and juvenile/adult form [43]. Recurrent clinical features in the three GSL types include coarse facies, hepatosplenomegaly, dysostosis multiplex, growth retardation associated with muscular atrophy, heart involvement with cardiomegaly and thickening of the mitral and aortic valves, hearing loss, and neurological disorders [43,120,121]. To date, 28 different CTSA gene mutations have been linked to GSL, including deletions, splicing, and missense mutations [114][115][116][117][118].…”