Identifying cellular pathways modulated by Drosophila palmitoyl-protein thioesterase 1 function

Abstract Infantile-onset Neuronal Ceroid Lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl-protein thioesterase 1 (Ppt1). This enzyme is responsible for the removal of a palmitate post-translational modification from an unknow...

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Published in:	Neurobiology of disease Vol. 40; no. 1; pp. 135 - 145
Main Authors:	Saja, Stephanie, Buff, Haley, Smith, Alexis C, Williams, Tiffany S, Korey, Christopher A
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-10-2010 Elsevier
Subjects:	Animals Animals, Genetically Modified Batten Disease Cells, Cultured Drosophila Drosophila melanogaster - cytology Drosophila melanogaster - enzymology Drosophila melanogaster - genetics Drosophila models Drosophila Proteins - genetics Drosophila Proteins - physiology Endocytosis Membrane Proteins - genetics Membrane Proteins - physiology Mutation - genetics Neural Pathways - metabolism Neural Pathways - physiology Neurology Neuronal Ceroid Lipofuscinosis Neuronal Plasticity - genetics Neurons - enzymology Palmitoyl-protein thioesterase 1 Palmitoylation Photoreceptor Cells, Invertebrate - physiology Protein Transport - genetics Trafficking Transport Vesicles - physiology Endocytosis Neuronal Ceroid Lipofuscinosis Palmitoylation Batten Disease Trafficking Palmitoyl-protein thioesterase 1 Drosophila models
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Summary:	Abstract Infantile-onset Neuronal Ceroid Lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl-protein thioesterase 1 (Ppt1). This enzyme is responsible for the removal of a palmitate post-translational modification from an unknown set of substrate proteins. To better understand the function of Ppt1 in neurons, we performed an unbiased dominant loss-of-function genetic modifier screen in Drosophila using a previously characterized Ppt1 gain-of-function system. The enhancers and suppressors identified in our screen make novel connections between Ppt1 and genes involved in cellular trafficking and the modulation of synaptic growth. We further support the relevance of our screen by demonstrating that Garland cells from Ppt1 loss-of-function mutants have defects in endocytic trafficking. Endocytic tracer uptake and ultrastructural analysis of these non-neuronal cells points to Ppt1 playing a role in modulating the early stages of vesicle formation. This work lays the groundwork for further experimental exploration of these processes to better understand their contributions to the INCL disease process.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 These authors contributed equally to this work
ISSN:	0969-9961 1095-953X
DOI:	10.1016/j.nbd.2010.02.010