title: Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses.
abstract: Neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage disorders characterized pathologically by neuronal accumulation of autofluorescent storage material and neurodegeneration. An ovine NCL form is caused by a recessive point mutation in the cathepsin D gene, which encodes a lysosomal aspartyl protease. This mutation results in typical NCL pathology with neurodegeneration and characteristic neuronal storage material. We have generated a Drosophila NCL model by inactivating the conserved Drosophila cathepsin D homolog. We report here that cathepsin D mutant flies exhibit the key features of NCLs. They show progressive neuronal accumulation of autofluorescent storage inclusions, which are also positive for periodic acid Schiff and luxol fast blue stains. Ultrastructurally, the storage material is composed of membrane-bound granular electron-dense material, similar to the granular osmiophilic deposits found in the human infantile and ovine congenital NCL forms. In addition, cathepsin D mutant flies show modest age-dependent neurodegeneration. Our results suggest that the metabolic pathway leading to NCL pathology is highly conserved during evolution, and that cathepsin D mutant flies can be used to study the pathogenesis of NCLs.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB Room 652, Boston, MA 02115, USA.
authors.forename: Liisa
authors.initials: L
authors.lastname: Myllykangas
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.forename: Andrea
authors.initials: A
authors.lastname: Page-McCaw
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Rubin
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Haltia
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster; D008969:Molecular Sequence Data; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D002402:Cathepsin D