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

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Cathepsin B (CTSB) and cathepsin L (CTSL) are two widelyexpressed cysteine proteases thought to predominantly reside withinlysosomes. Functional analysis of CTSL in humans is complicated by theexistence of two CTSL-like homologues (CTSL and CTSL2), in contrast tomice which contain only one CTSL enzyme. Thus transgenic expression ofhuman CTSL in CTSL deficient mice provides an opportunity to study the invivo functions of this human protease without interference by its highlyrelated homologue. While mice with single gene deficiencies for murineCTSB or CTSL survive without apparent neuromuscular impairment, murineCTSB/CTSL double deficient mice display degeneration of cerebellarPurkinje cells and neurons of the cerebral cortex, ... continued below

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Sevenich, Lisa; Pennacchio, Len A.; Peters, Christoph & Reinheckel, Thomas January 9, 2006.

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Cathepsin B (CTSB) and cathepsin L (CTSL) are two widelyexpressed cysteine proteases thought to predominantly reside withinlysosomes. Functional analysis of CTSL in humans is complicated by theexistence of two CTSL-like homologues (CTSL and CTSL2), in contrast tomice which contain only one CTSL enzyme. Thus transgenic expression ofhuman CTSL in CTSL deficient mice provides an opportunity to study the invivo functions of this human protease without interference by its highlyrelated homologue. While mice with single gene deficiencies for murineCTSB or CTSL survive without apparent neuromuscular impairment, murineCTSB/CTSL double deficient mice display degeneration of cerebellarPurkinje cells and neurons of the cerebral cortex, resulting in severehypotrophy, motility defects, and lethality during their third to fourthweek of life. Here we show that expression of human CTSL through agenomic transgene results in widespread expression of human CTSL in themouse which is capable of rescuing the lethality found in CTSB/CTSLdouble-deficient animals. Human CTSL is expressed in the brain of thesecompound mutants predominantly in neurons of the cerebral cortex and inPurkinje cells of the cerebellum, where it appears to prevent neuronalcell death.

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  • Journal Name: Biological Chemistry; Journal Volume: 387; Journal Issue: 7; Related Information: Journal Publication Date: 07/2006

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  • Report No.: LBNL--59312
  • Grant Number: DE-AC02-05CH11231
  • DOI: 10.1515/BC.2006.112 | External Link
  • Office of Scientific & Technical Information Report Number: 927243
  • Archival Resource Key: ark:/67531/metadc896009

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  • January 9, 2006

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  • Sept. 27, 2016, 1:39 a.m.

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Sevenich, Lisa; Pennacchio, Len A.; Peters, Christoph & Reinheckel, Thomas. Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice, article, January 9, 2006; United States. (digital.library.unt.edu/ark:/67531/metadc896009/: accessed August 21, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.