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Licensed Unlicensed Requires Authentication Published by De Gruyter July 20, 2006

Human cathepsin L rescues the neurodegeneration and lethality in cathepsin B/L double-deficient mice

Lisa Sevenich , Len A. Pennacchio , Christoph Peters and Thomas Reinheckel
From the journal


Cathepsin B (CTSB) and cathepsin L (CTSL) are two widely expressed cysteine proteases thought to predominantly reside within lysosomes. Functional analysis of CTSL in humans is complicated by the existence of two CTSL-like homologs (CTSL and CTSL2), in contrast to mice, which possess only one CTSL enzyme. Thus, transgenic expression of human CTSL in CTSL-deficient mice provides an opportunity to study the in vivo functions of this human protease without interference by its highly related homolog. While mice with single-gene deficiencies for murine CTSB or CTSL survive without apparent neuromuscular impairment, murine CTSB/CTSL double-deficient mice display degeneration of cerebellar Purkinje cells and neurons of the cerebral cortex, resulting in severe hypotrophy, motility defects, and lethality during their third to fourth week of life. Here we show that expression of human CTSL through a genomic transgene results in widespread expression of human CTSL in the mouse that is capable of rescuing the lethality found in CTSB/CTSL double-deficient animals. Human CTSL is expressed in the brain of these compound mutants, predominantly in neurons of the cerebral cortex and in Purkinje cells of the cerebellum, where it appears to prevent neuronal cell death.


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Brömme, D. and Kaleta, J. (2002). Thiol-dependent cathepsins: pathophysiological implications and recent advances in inhibitor design. Curr. Pharm. Des.8, 1639–1658.10.2174/1381612023394179Search in Google Scholar PubMed

Ciechanover, A. (2005). Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol.6, 79–87.10.1038/nrm1552Search in Google Scholar PubMed

Felbor, U., Kessler, B., Mothes, W., Goebel, H.H., Ploegh, H.L., Bronson, R.T., and Olsen, B.R. (2002). Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl. Acad. Sci. USA99, 7883–7888.10.1073/pnas.112632299Search in Google Scholar PubMed PubMed Central

Friedrichs, B., Tepel, C., Reinheckel, T., Deussing, J., von Figura, K., Herzog, V., Peters, C., Saftig, P., and Brix, K. (2003). Thyroid functions of mouse cathepsins B, K, and L. J. Clin. Invest.111, 1733–1745.10.1172/JCI15990Search in Google Scholar PubMed PubMed Central

Guicciardi, M.E., Deussing, J., Miyoshi, H., Bronk, S.F., Svingen, P.A., Peters, C., Kaufmann, S.H., and Gores, G.J. (2000). Cathepsin B contributes to TNF-α-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J. Clin. Invest.106, 1127–1137.10.1172/JCI9914Search in Google Scholar PubMed PubMed Central

Hagemann, S., Gunther, T., Dennemarker, J., Lohmuller, T., Brömme, D., Schule, R., Peters, C., and Reinheckel, T. (2004). The human cysteine protease cathepsin V can compensate for murine cathepsin L in mouse epidermis and hair follicles. Eur. J. Cell Biol.83, 775–780.10.1078/0171-9335-00404Search in Google Scholar PubMed

Halangk, W., Lerch, M.M., Brandt-Nedelev, B., Roth, W., Ruthenbuerger, M., Reinheckel, T., Domschke, W., Lippert, H., Peters, C., and Deussing, J. (2000). Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J. Clin. Invest.106, 773–781.10.1172/JCI9411Search in Google Scholar PubMed PubMed Central

Honey, K., Nakagawa, T., Peters, C., and Rudensky, A. (2002). Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med.195, 1349–1358.10.1084/jem.20011904Search in Google Scholar PubMed PubMed Central

Hook, V., Yasothornsrikul, S., Greenbaum, D., Medzihradszky, K.F., Troutner, K., Toneff, T., Bundey, R., Logrinova, A., Reinheckel, T., Peters, C., and Bogyo, M. (2004). Cathepsin L and Arg/Lys aminopeptidase: a distinct prohormone processing pathway for the biosynthesis of peptide neurotransmitters and hormones. Biol. Chem.385, 473–480.10.1515/BC.2004.055Search in Google Scholar PubMed

Hook, V., Toneff, T., Bogyo, M., Greenbaum, D., Medzihradszky, K.F., Neveu, J., Lane, W., Hook, G., and Reisine, T. (2005). Inhibition of cathepsin B reduces β-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate β-secretase of Alzheimer's disease. Biol. Chem.386, 931–940.Search in Google Scholar

Houseweart, M.K., Pennacchio, L.A., Vilaythong, A., Peters, C., Noebels, J.L., and Myers, R.M. (2003). Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). J. Neurobiol.56, 315–327.10.1002/neu.10253Search in Google Scholar PubMed

Lieuallen, K., Pennacchio, L.A., Park, M., Myers, R.M., and Lennon, G.G. (2001). Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. Hum. Mol. Genet.10, 1867–1871.10.1093/hmg/10.18.1867Search in Google Scholar

Nakagawa, T., Roth, W., Wong, P., Nelson, A., Farr, A., Deussing, J., Villadangos, J.A., Ploegh, H., Peters, C., and Rudensky, A.Y. (1998). Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science280, 450–453.10.1126/science.280.5362.450Search in Google Scholar

Olsson, T., Nygren, J., Hakansson, K., Lundblad, C., Grubb, A., Smith, M.L., and Wieloch, T. (2004). Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse. Neuroscience128, 65–71.10.1016/j.neuroscience.2004.06.024Search in Google Scholar

Pennacchio, L.A., Lehesjoki, A.E., Stone, N.E., Willour, V.L., Virtaneva, K., Miao, J., D'Amato, E., Ramirez, L., Faham, M., Koskiniemi, M., et al. (1996). Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science271, 1731–1734.10.1126/science.271.5256.1731Search in Google Scholar

Pennacchio, L.A., Bouley, D.M., Higgins, K.M., Scott, M.P., Noebels, J.L., and Myers, R.M. (1998). Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat. Genet.20, 251–258.10.1038/3059Search in Google Scholar

Reinheckel, T., Deussing, J., Roth, W., and Peters, C. (2001). Towards specific functions of lysosomal cysteine peptidases: phenotypes of mice deficient for cathepsin B or cathepsin L. Biol. Chem.382, 735–741.Search in Google Scholar

Reinheckel, T., Hagemann, S., Dollwet-Mack, S., Martinez, E., Lohmuller, T., Zlatkovic, G., Tobin, D.J., Maas-Szabowski, N., and Peters, C. (2005). The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling. J. Cell Sci.118, 3387–3395.10.1242/jcs.02469Search in Google Scholar

Roth, W., Deussing, J., Botchkarev, V.A., Pauly-Evers, M., Saftig, P., Hafner, A., Schmidt, P., Schmahl, W., Scherer, J., Anton-Lamprecht, I., et al. (2000). Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J.14, 2075–2086.10.1096/fj.99-0970comSearch in Google Scholar

Stypmann, J., Glaser, K., Roth, W., Tobin, D.J., Petermann, I., Matthias, R., Monnig, G., Haverkamp, W., Breithardt, G., Schmahl, W., et al. (2002). Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Natl. Acad. Sci. USA99, 6234–6239.10.1073/pnas.092637699Search in Google Scholar

Tobin, D.J., Foitzik, K., Reinheckel, T., Mecklenburg, L., Botchkarev, V.A., Peters, C., and Paus, R. (2002). The lysosomal protease cathepsin L is an important regulator of keratinocyte and melanocyte differentiation during hair follicle morphogenesis and cycling. Am. J. Pathol.160, 1807–1821.10.1016/S0002-9440(10)61127-3Search in Google Scholar

Turk, V., Turk, B., and Turk, D. (2001). Lysosomal cysteine proteases: facts and opportunities. EMBO J.20, 4629–4633.10.1093/emboj/20.17.4629Search in Google Scholar PubMed PubMed Central

Urbich, C., Heeschen, C., Aicher, A., Sasaki, K., Bruhl, T., Farhadi, M.R., Vajkoczy, P., Hofmann, W.K., Peters, C., Pennacchio, L.A., et al. (2005). Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat. Med.11, 206–213.10.1038/nm1182Search in Google Scholar PubMed

Yasothornsrikul, S., Greenbaum, D., Medzihradszky, K.F., Toneff, T., Bundey, R., Miller, R., Schilling, B., Petermann, I., Dehnert, J., Logvinova, A., et al. (2003). Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter. Proc. Natl. Acad. Sci. USA100, 9590–9595.10.1073/pnas.1531542100Search in Google Scholar PubMed PubMed Central

Published Online: 2006-07-20
Published in Print: 2006-07-01

©2006 by Walter de Gruyter Berlin New York

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