title: Palmitoyl-protein thioesterase 1 deficiency in Drosophila melanogaster causes accumulation of abnormal storage material and reduced life span.
abstract: Human neuronal ceroid lipofuscinoses (NCLs) are a group of genetic neurodegenerative diseases characterized by progressive death of neurons in the central nervous system (CNS) and accumulation of abnormal lysosomal storage material. Infantile NCL (INCL), the most severe form of NCL, is caused by mutations in the Ppt1 gene, which encodes the lysosomal enzyme palmitoyl-protein thioesterase 1 (Ppt1). We generated mutations in the Ppt1 ortholog of Drosophila melanogaster to characterize phenotypes caused by Ppt1 deficiency in flies. Ppt1-deficient flies accumulate abnormal autofluorescent storage material predominantly in the adult CNS and have a life span 30% shorter than wild type, phenotypes that generally recapitulate disease-associated phenotypes common to all forms of NCL. In contrast, some phenotypes of Ppt1-deficient flies differed from those observed in human INCL. Storage material in flies appeared as highly laminar spherical deposits in cells of the brain and as curvilinear profiles in cells of the thoracic ganglion. This contrasts with the granular deposits characteristic of human INCL. In addition, the reduced life span of Ppt1-deficient flies is not caused by progressive death of CNS neurons. No changes in brain morphology or increases in apoptotic cell death of CNS neurons were detected in Ppt1-deficient flies, even at advanced ages. Thus, Ppt1-deficient flies accumulate abnormal storage material and have a shortened life span without evidence of concomitant neurodegeneration.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany 12201-2002, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
authors.forename: Heather L
authors.initials: HL
authors.lastname: Chotkowski
authors.forename: Navjot
authors.initials: N
authors.lastname: Singh
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Ault
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Korey
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Robert L
authors.initials: RL
authors.lastname: Glaser
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D005260:Female; D008297:Male; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000502:physiology*
chemical_list: D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase