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

Abstract

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.

Authors:
; ; ;
Publication Date:
Research Org.:
COLLABORATION - Institut fur Molekulare Medizinund Zellforschung, Albert-Ludwigs-Universitat Freiburg,Germany
OSTI Identifier:
927243
Report Number(s):
LBNL-59312
R&D Project: GHPG4B; TRN: US200811%%65
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biological Chemistry; Journal Volume: 387; Journal Issue: 7; Related Information: Journal Publication Date: 07/2006
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ANIMALS; BRAIN; CATHEPSINS; CEREBELLUM; CEREBRAL CORTEX; CYSTEINE; DEATH; DEFECTS; FUNCTIONAL ANALYSIS; GENES; IN VIVO; LYSOSOMES; MICE; MUTANTS; NERVE CELLS; Cathepsin, Neurodegeneration, Purkinje cell

Citation Formats

Sevenich, Lisa, Pennacchio, Len A., Peters, Christoph, and Reinheckel, Thomas. Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice. United States: N. p., 2006. Web. doi:10.1515/BC.2006.112.
Sevenich, Lisa, Pennacchio, Len A., Peters, Christoph, & Reinheckel, Thomas. Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice. United States. doi:10.1515/BC.2006.112.
Sevenich, Lisa, Pennacchio, Len A., Peters, Christoph, and Reinheckel, Thomas. Mon . "Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice". United States. doi:10.1515/BC.2006.112. https://www.osti.gov/servlets/purl/927243.
@article{osti_927243,
title = {Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice},
author = {Sevenich, Lisa and Pennacchio, Len A. and Peters, Christoph and Reinheckel, Thomas},
abstractNote = {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.},
doi = {10.1515/BC.2006.112},
journal = {Biological Chemistry},
number = 7,
volume = 387,
place = {United States},
year = {Mon Jan 09 00:00:00 EST 2006},
month = {Mon Jan 09 00:00:00 EST 2006}
}