Cathepsin deficiency

The protective antiprotease -antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarettesmoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases. In addition, oxidative stress reduces antiprotease (or protective) activity. 

Gelb BD, Shi GP, Chapman FIA et al (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273 1236-1238... 

Cathepsin L-deficient mice show decreased levels of enkephalin in the brain, with reduction by approximately one half (22). In addition, enkephalin brain levels are also reduced by about one half in PC2-deficient mice (28). These results support dual roles for both cathepsin L and PC2 in enkephalin production. Ongoing studies indicate multiple neuropeptides that are substantially decreased by more than 50% in the brain and endocrine tissues of cathepsin L knockout mice (Eunkelstein et al., submitted for publication). With the observed alterations in brain neuropeptides, it will be of interest in future studies to assess the behavioral effects of the loss of neuropeptides in cathepsin L knockout mice. Cathepsin L knockout mice are viable and show phenotypes of hair loss and cardiac myopathy (29, 30). The mechanism for these functional effects of cathepsin L deficiency could possibly involve neuropeptides. New and continued investigations of neuropeptides in cathepsin L knockout mice will provide knowledge of the relative roles of cathepsin L in the production of particular neuropeptides. 

A review of neuropeptide data from PC2 and PCl/3 knockout mice shows that the majority of neuropeptides studies are partially reduced in the knockout compared with wild-type controls. These results indicate roles for PC2 and PCl/3 in neuropeptide production. Importantly, the partial reduction of neuropeptides examined in PC2- and PC 1/3-deficient mice also indicates possible roles for other proteases for processing proneuropeptides, such as cathepsin L in secretory vesicles for neuropeptide production that has been discussed in this article. Thus, the chemical biology approach has identified fhe novel cafhepsin L cysfeine protease pafhway as a candidafe route for neuropeptide production. 

More specifically, fo integrate data from PC2- and PCl/3-deficient mouse studies with recent data that demonstrate a candidate role for cathepsin L in neuropeptide production, results of neuropeptides studied in PC 2- and PC 1/3-deficient mice are summarized here. In PC2 knockout mice, many neuropeptides were partially reduced, with the exception of a-MSH that was nearly obliterated. PC2-deficient mice show increases in the POMC-derived peptide hormones ACTH and 3-endorphin (1-31), which identifies fhem as subsfrafes for PC2 (40). Among fhe POMC-derived peptide hormones, only a-MSH was nearly complefely absenf in the PC2 knockout (40). NPY was unchanged in the brain but was decreased in ileum and was increased in adrenal (41). Somatostatin was increased in the brain and was unchanged in the intestine (Met)enkephalin was partially decreased in the brain but was not altered in adrenal and intestinal tissues. (41). No changes in VIP, galanin, or CRF were observed in PC2-deficient mice. Insulin in the pancreas was reduced by 75% compared with wild-type controls, and... 

These findings demonstrate several features with regard to the selective roles of PC2 and PCl/3 in determining the production of neuropeptides. Firstly, PC-deficient mice may show changes in several neuropeptides but not all neuropeptides. Secondly, neuropeptides may show tissue-specific differences in PC-deficient mice. Thirdly, a particular tissue region may show selective alterations among different neuropeptides in each of the PC-deficient mice. These results demonstrate the roles of PC2 and PCl/3 in neuropeptide production. Notably, partial reductions of many neuropeptides in mice deficient in PC2 or PCl/3 are consistent with the presence of other processing enzymes such as the newly identified cathepsin L protease pathway for neuropeptide production. 

Stypmann J, Glaser K, Roth W, Tobin DJ, Petermann I, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Natl. Acad. Sci. U.S.A. 2002 99 6234-6239. 

Increased concentrations of muscle cathepsins have been recorded in many types of muscle atrophy. Acid cathepsin activity increases in dystrophic mouse muscle (W12) and in muscle from Duchenne-type dystrophy (P6) in the latter investigation, the elevation tended to be greater in the more advanced cases. Elevated acid cathepsin has been recorded also in denervation atrophy and vitamin E deficiency. Alkaline cathepsin activity has been shown to be higher in the dystrophic mouse (P7) and in Duchenne dystrophy (P12). 

Sukhoya GK, Zhang Y, Pan JH, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2003 111 897-906. Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vase Biol 2001 21 1440-1445. 

There have been few discoveries of lysosomal storage diseases being related to a deficiency of a protease. Efficient lysosomal proteolysis could be such a crucial metabolic process that any defects in this system would be developmentally lethal and therefore never observed medically. For example, mice deficient in cathepsin D were generated by targeted disruption of the gene and the animals died in a state of anorexia by day 26 due to widespread intestinal necroses [42]. Since bulk lysosomal... 

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