title: Neuroectoderm-specific deletion of cathepsin D in mice models human inherited neuronal ceroid lipofuscinosis type 10.
abstract: Cathepsin D (Ctsd) is a ubiquitously expressed aspartic protease functioning primarily in the acidic endosomal/lysosomal cell compartment. At an age of 26 ± 1 days, mice with constitutive Ctsd deficiency (Ctsd(-/-)) die from a neurodegenerative lysosomal storage disease equivalent to the congenital neuronal ceroid lipofuscinosis (NCL) type 10 in humans. In addition to neurodegeneration, Ctsd(-/-) mice exhibit a loss of CD4(+)/CD8(+)-double-positive thymocytes and an atrophy of the intestinal mucosa. To date, it is not understood if and how these phenotypes are triggering each other. In addition, the cell type causing initiation of NCL in Ctsd(-/-) mice has not been identified yet. To investigate the tissue- and cell type-specific functions of Ctsd, we generated a novel conditional Ctsd allele by flanking the second exon with loxP sites. We compared a ubiquitous Ctsd deletion with a deletion of the protease by a Nestin-promoter controlled Cre-recombinase expression in cells of neuroectodermal origin, e.g. in neurons and astroglia, but not in microglia. First, we confirmed absence of Ctsd in the respective cell- and tissue types. The neuroectoderm specific knock-out mice survived about 5.5 days longer than the mice with ubiquitous Ctsd deletion, which was in line with the progress in brain histopathology. Atrophies of thymus and small intestine were delayed to similar extend. The conditional Ctsd knock-out mouse model established in this study not only demonstrates that this type of NCL is initiated by cells of neuroectodermal origin, but will also help to further study tissue-specific functions of Ctsd in vivo.
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Ketscher
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany; German Cancer Consortium (DKTK), D-79106 Freiburg, Germany; German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ketterer
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Dollwet-Mack
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Reif
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany; German Cancer Consortium (DKTK), D-79106 Freiburg, Germany; German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany. Electronic address: thomas.reinheckel@uniklinik-freiburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D001284:Atrophy / Q000235:genetics; D015153:Blotting, Western; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004475:Ectoderm / Q000378:metabolism*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D054259:Neural Tube / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology* / Q000235:genetics; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013950:Thymus Gland / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D002402:Cathepsin D
keywords: Cathepsin D; Conditional knock-out; Neurodegenerative disease; Neuronal lipofuscinosis