Cathepsin K functions in the mouse central nervous system

  • Cathepsin K is a cysteine protease well known for its importance in bone remodeling and inhibitors of cathepsin K are currently in clinical trials for osteoporosis treatment. However, severe side effects were induced by cathepsin K inhibitor treatment of rats or mice affecting both, peripheral organs and the central nervous system (CNS). This is due to the fact that cathepsin K has also been detected in brain parenchyma only recently. Lately, we have shown that cathepsin K deficiency in mice induces structural and functional alterations in the CNS which are associated with learning and memory deficits. Furthermore, the proteolytic network was deregulated in the brain of cathepsin K-deficient (Ctsk-/-) animals. Moreover, astroglia-rich primary cell cultures from Ctsk-/- mice revealed an increase in enzymes of the glutathione metabolism, as well as elevated numbers of oligodendrocytes compared to wild type controls. Thus, we propose that cathepsin K contributes significantly to cellular and molecular homeostasis of the CNS. Cathepsin K was also demonstrated to bear a vital function in the thyroid gland, because it contributes to thyroid hormone (TH) liberation. THs are well known to be crucial for proper CNS development and its maintenance during adulthood. Therefore, we hypothesized that brain and thyroid functions of cathepsin K might be linked. However, our results suggest that Ctsk-/- mice do not suffer from classical hypothyroidism. Interestingly, trace amine-associated receptor 1 as well as TH transporters were found to be deregulated in the CNS of Ctsk-/- mice. Since all markers of classical thyroid regulation were comparable in wild type and Ctsk-/- mice, but markers of non-classical thyroid regulation differed significantly, we believe to have identified an animal model suited to study non-classical TH actions on the CNS in addition to serving as a mouse model for studying the general functions of cathepsin K in the CNS.

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Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Stephanie Dauth
Referee:Klaudia Brix, Matthias Ullrich, Benjamin Godde, U. Schweizer
Advisor:Klaudia Brix
Persistent Identifier (URN):urn:nbn:de:101:1-201305294530
Document Type:PhD Thesis
Language:English
Date of Successful Oral Defense:2012/04/19
Year of Completion:2012
Date of First Publication:2012/05/24
PhD Degree:Cell Biology
School:SES School of Engineering and Science
Library of Congress Classification:Q Science / QP Physiology / QP501-801 Animal biochemistry / QP525-801 Special substances / QP550-801 Organic substances / QP551-619 Proteins, amino acids, etc. / QP601-619 Enzymes / QP608-609 Hydrolases / QP609.A-Z Special, A-Z / QP609.C35 Cathepsin
Call No:Thesis 2012/7

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