Identification and characterization of Caenorhabditis elegans palmitoyl protein thioesterase1.
Infantile neuronal ceroid lipofuscinosis (INCL; Batten disease) is a severe neurodegenerative disorder of childhood characterized by the accumulation of autofluorescent storage material in lysosomes. It is caused by mutation of the CLN1/PPT1 gene, which encodes the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1), but the mechanism of disease pathogenesis and substrates for the enzyme are unknown. Caenorhabditis elegans is a simple nematode worm, with a fully sequenced genome, which is easy to maintain and manipulate. It has a completely mapped cell lineage and nervous system and has already provided clues about the pathogenesis of several human neuronal and lysosomal storage disorders. We have identified and characterized a PPT1 homologue in C. elegans. We found that, although this gene was not essential for the animal's survival, its mutation resulted in a mild developmental and reproductive phenotype, affected the number and size of mitochondria, and resulted in an abnormality in mitochondrial morphology, possibly suggestive of a role for this organelle in INCL pathogenesis. This strain, deleted for ppt-1, potentially provides a model system for the study of PPT1 and the pathogenesis of INCL.
Porter
Morwenna Y
MY
Department of Paediatrics and Child Health, Royal Free and University College Medical School, University College London, London, United Kingdom.
Turmaine
Mark
M
Mole
Sara E
SE
D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified / Q000502:physiology; D015152:Blotting, Northern / Q000379:methods; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D048429:Cell Size; D019295:Computational Biology / Q000379:methods; D006801:Humans; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012098:Reproduction / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA / Q000379:methods; D017385:Sequence Homology; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D012333:RNA, Messenger; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D001616:beta-Galactosidase; D001619:beta-N-Acetylhexosaminidases