Research Article Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations O. Y. Calhan and V. Seyrantepe Department of Molecular Biology and Genetics, Izmir Institute of Technology, Gulbahce Mahallesi, Urla, Izmir, Turkey Correspondence should be addressed to V. Seyrantepe; volkanseyrantepe@iyte.edu.tr Received 9 September 2016; Accepted 5 December 2016; Published 4 January 2017 Academic Editor: Barbara Picconi Copyright © 2017 O. Y. Calhan and V. Seyrantepe. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protects - galactosidase and sialidase Neu1 against proteolytic degradation by forming a multienzyme complex and activates sialidase Neu1. CathA defciency causes the lysosomal storage disease, galactosialidosis. Tese 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 specifc activity against vasoactive peptides and neuropeptides, including endothelin-1 and oxytocin. A mutant mouse with catalytically inactive CathA enzyme (ℎ 190 ) 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 ℎ 190 mice, which showed learning impairments as well as long-term and spatial memory defcits compared with wild-type littermates, suggesting that CathA plays a signifcant role in learning and in memory consolidation through its regulatory role in vasoactive peptide processing. 1. Introduction Cathepsin A (CathA) is a ubiquitously expressed component of a lysosomal multienzyme complex (LMC) with indepen- dent protective and catalytic functions [1, 2]. CathA is a member of the serine protease family of enzymes, with carboxypeptidase activity at pH 5.5 and deamidase and esterase activity at pH 7.0 [3]. CathA protects sialidase 1 (also known as Neu1) and -galactosidase (-Gal) glycosidases against proteolytic degradation by the composition of the LMC and activates Neu1. Te complex is unable to form in the absence of CathA [4]. In vitro studies have shown that CathA has catalytic activity against several vasoactive peptides, including endothelin-1, angiotensin-1, and bradykinin, and some neuropeptides, such as oxytocin and substance P [5]. Genetic mutations in the CathA gene are characterized by the occurrence of the lysosomal storage disorder galactosiali- dosis, which involves a secondary defciency of Neu1 and - Gal [6]. It has also been demonstrated that CathA is involved in the inactivation of the lysosome-associated membrane protein type 2a (lamp2a) in chaperone-mediated autophagy [7]. Te efects of immunization to CathA on learning in a rat model inspired us to investigate whether catalytically inactive CathA has similar efects on behavior and memory [8]. Although the ℎ −/− knockout mouse model presents phenotypes similar to human patients with galactosialidosis, severe symptoms arising due to the secondary defciency of Neu1 and -Gal prevent the use of this mouse model for behavioral analysis [9]. Terefore, in this study, we used a previously generated ℎ 190 knock-in mouse model with a mutation in the catalytic site. Although catalytic enzyme activity is abolished in ℎ 190 mice, they are still able to form the LMC and activate Neu1 [10]. In this study, we analyzed the performance of ℎ 190 mice in learning- and memory-based tasks at three diferent ages. We observed decline in cognitive functions as well as in learning and memory in ℎ 190 mice. Afer reveal- ing the involvement of CathA in these behavioral changes, we investigated the levels of endothelin-1 and oxytocin in the ℎ 190 mouse brain. We demonstrated here for the frst time that the hippocampal region has highly elevated lev- els of the vasoactive peptides: endothelin-1, angiotensin-I, Hindawi Publishing Corporation Behavioural Neurology Volume 2017, Article ID 4261873, 11 pages http://dx.doi.org/10.1155/2017/4261873