Lysosomal cathepsins and their regulation in aging and neurodegeneration

Abstract

Lysosomes and lysosomal hydrolases, including the cathepsins, have been shown to change their properties with aging brain a long time ago, although their function was not really understood. The first biochemical and clinical studies were followed by a major expansion in the last 20 years with the development of animal disease models and new approaches leading to a major advancement of understanding of the role of physiological and degenerative processes in the brain at the molecular level. This includes the understanding of the major role of autophagy and the cathepsins in a number of diseases, including its critical role in the neuronal ceroid lipofuscinosis. Similarly, cathepsins and some other lysosomal proteases were shown to have important roles in processing and/or degradation of several important neuronal proteins, thereby having either neuroprotective or harmful roles. In this review, we discuss lysosomal cathepsins and their regulation with the focus on cysteine cathepsins and their endogenous inhibitors, as well as their role in several neurodegenerative diseases.

Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice

“…Previous research revealed enhanced [51, 59] as well reduced lysosomal enzyme activities [38, 39] in various Grn −/− cells types or tissue. Based on our findings, these discrepancies may be explained by different cell types analyzed, difficulties with the determination of specific activities of lysosomal enzymes due to their complex proteolytic processing and consequences for their proteolytic activity [53, 61]. Single chain variants as well as dimeric variants of heavy and light chain are catalytically active whereas separated heavy and light chains are inactive [53, 61].…”

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

“…Thus, in order to design a powerful and specific Cathepsin inhibitor, it is of fundamental importance to have detailed knowledge of the features of each sub-site of each Cathepsin [37][38][39]. In addition, it is worth highlighting that this class of enzyme is related to several pathological processes such as osteoporosis (Cathepsin K) [40,41], neurodegenerative disease (Cathepsin D) [42] and metastasis in several types of cancer (Cathepsins B, K, L and S) [43][44][45]. Hence, Cathepsins are promising targets for the treatment of such disorders [46].…”

Serpin1 and WSCP differentially regulate the activity of the cysteine protease RD21 during plant development in Arabidopsis thaliana

“…Elevated protease expression was found to be associated with poor patient prognosis across numerous tumor types (29). Other studies demonstrated important roles of lysosomal cysteine cathepsins in aging and neurodegeneration (30). Last but not least, cysteine cathepsins were reported to trigger caspase-dependent cell death through cleavage of BID (BH3 interacting-domain death agonist) and antiapoptotic Bcl-2 (B-cell lymphoma 2) homologs (31).…”