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Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations
1Department of Molecular Biology and Genetics, Izmir Institute of Technology, Gulbahce Mahallesi, Urla, Izmir, Turkey.
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 (CathA ) 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 CathA 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.
Insights
Cathepsin A (CathA) deficiency impairs learning and memory by causing vasoactive peptide buildup in the brain. This study reveals CathA
Area of Science:
- Neuroscience
- Biochemistry
- Lysosomal Storage Diseases
Background:
- Cathepsin A (CathA) is a lysosomal carboxypeptidase crucial for enzyme stability and activation.
- CathA deficiency leads to galactosialidosis, characterized by neurological deterioration and peptide accumulation.
- Previous studies indicated CathA's role in processing vasoactive peptides like endothelin-1.
Purpose of the Study:
- To investigate the role of CathA in learning and memory.
- To examine the impact of CathA deficiency on neuropeptide levels in the brain.
- To understand CathA's function in cognitive processes.
Main Methods:
- Utilized a catalytically inactive CathA mutant mouse model (CathA-/-).
- Assessed learning, long-term memory, and spatial memory in 3-, 6-, and 12-month-old mice.
- Quantified hippocampal levels of endothelin-1 and oxytocin.
Main Results:
- CathA-/- mice exhibited significant learning and memory deficits compared to wild-type littermates.
- Accumulation of endothelin-1 and oxytocin was observed in the hippocampi of CathA-/- mice.
- Deficits were noted across different age groups, indicating a persistent role of CathA.
Conclusions:
- CathA plays a critical role in learning and memory consolidation.
- The regulatory function of CathA in processing vasoactive peptides is essential for cognitive function.
- CathA deficiency contributes to cognitive impairment through altered neuropeptide signaling.
