Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits

Abstract

BackgroundCathepsin K is a cysteine peptidase known for its importance in osteoclast-mediated bone resorption. Inhibitors of cathepsin K are in clinical trials for treatment of osteoporosis. However, side effects of first generation inhibitors included altered levels of related cathepsins in peripheral organs and in the central nervous system (CNS). Cathepsin K has been recently detected in brain parenchyma and it has been linked to neurobehavioral disorders such as schizophrenia. Thus, the study of the functions that cathepsin K fulfils in the brain becomes highly relevant.ResultsCathepsin K messenger RNA was detectable in all brain regions of wild type (WT) mice. At the protein level, cathepsin K was detected by immunofluorescence microscopy in vesicles of neuronal and non-neuronal cells throughout the mouse brain. The hippocampus of WT mice exhibited the highest levels of cathepsin K activity in fluorogenic assays, while the cortex, striatum, and cerebellum revealed significantly lower enzymatic activities. At the molecular level, the proteolytic network of cysteine cathepsins was disrupted in the brain of cathepsin K-deficient (Ctsk-/-) animals. Specifically, cathepsin B and L protein and activity levels were altered, whereas cathepsin D remained largely unaffected. Cystatin C, an endogenous inhibitor of cysteine cathepsins, was elevated in the striatum and hippocampus, pointing to regional differences in the tissue response to Ctsk ablation. Decreased levels of astrocytic glial fibrillary acidic protein, fewer and less ramified profiles of astrocyte processes, differentially altered levels of oligodendrocytic cyclic nucleotide phosphodiesterase, as well as alterations in the patterning of neuronal cell layers were observed in the hippocampus of Ctsk-/- mice. A number of molecular and cellular changes were detected in other brain regions, including the cortex, striatum/mesencephalon, and cerebellum. Moreover, an overall induction of the dopaminergic system was found in Ctsk-/- animals which exhibited reduced anxiety levels as well as short- and long-term memory impairments in behavioral assessments.ConclusionWe conclude that deletion of the Ctsk gene can lead to deregulation of related proteases, resulting in a wide range of molecular and cellular changes in the CNS with severe consequences for tissue homeostasis. We propose that cathepsin K activity has an important impact on the development and maintenance of the CNS in mice.

Structural basis of collagen fiber degradation by cathepsin K

“…Exosite I partially overlaps with the protein dimer interaction site described in this report. This approach may exert an advantage over active-site inhibitors of CatK (36), as the therapeutic blocking of the hydrolysis of noncollagen substrates may give rise to adverse side effects as recently suggested (7) and corroborated by the finding that CatK-deficient mice show severe cognitive malfunction (37).…”

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

“…Furthermore, recent understanding of protease functions also includes numerous roles in cellular signaling, thus adding even further to the complexity (Turk and Stoka 2007). To study proteases in specific cellular contexts was the next step that addressed protease activities in different cell types, tissues, or animal models (Akkari et al 2014;Arampatzidou et al 2012;Chan et al 2009;Dauth et al 2011b;Friedrichs et al 2003;Gansz et al 2013;Nakagawa and Rudensky 1999;Reinheckel et al 2001;Sevenich et al 2014;Tamhane et al 2014). Understanding proteolysis in a larger context now includes focusing on the genes encoding proteolytic enzymes including transcriptional and translational regulation (Reiser et al 2010).…”

Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice

“…Studies with mouse models led to proposed functions of cathepsin K in adipogenesis, adipocyte differentiation, and regulation of glucose metabolism (Yang et al , 2008 ). In the central nervous system (CNS) of man and mouse, cathepsin K was found to be present in choroid plexus epithelial cells (Haeckel et al , 1999 ), neurons and glial cells (Lendeckel et al , 2009 ;Dauth et al , 2011b ).…”