Palmitoyl-Protein Thioesterase 1 Deficiency in Drosophila melanogaster Causes Accumulation of Abnormal Storage Material and Reduced Life Span

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 mut...

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Published in:Genetics (Austin) 2006-04, Vol.172 (4), p.2379-2390
Main Authors: Hickey, Anthony J, Chotkowski, Heather L, Singh, Navjot, Ault, Jeffrey G, Korey, Christopher A, MacDonald, Marcy E, Glaser, Robert L
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Disease Models, Animal
Drosophila melanogaster
Drosophila melanogaster - genetics
Drosophila melanogaster - physiology
Female
Functions
Genes
Investigations
Male
Microscopy, Electron
Microscopy, Fluorescence
Mutation
Neurodegenerative Diseases - metabolism
Neurological disorders
Neuronal Ceroid-Lipofuscinoses - metabolism
Neurons - metabolism
Phenotype
Proteins
RNA Interference
Thiolester Hydrolases - genetics
Thiolester Hydrolases - physiology
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Summary: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.
ISSN:0016-6731
1943-2631
1943-2631
DOI:10.1534/genetics.105.053306