PMID- 17409080 OWN - NLM STAT- MEDLINE DCOM- 20070913 LR - 20181201 IS - 0016-6731 (Print) IS - 0016-6731 (Linking) VI - 176 IP - 1 DP - 2007 May TI - Genetic modifiers of Drosophila palmitoyl-protein thioesterase 1-induced degeneration. PG - 209-20 AB - Infantile neuronal ceroid lipofuscinosis (INCL) is a pediatric neurodegenerative disease caused by mutations in the human CLN1 gene. CLN1 encodes palmitoyl-protein thioesterase 1 (PPT1), suggesting an important role for the regulation of palmitoylation in normal neuronal function. To further elucidate Ppt1 function, we performed a gain-of-function modifier screen in Drosophila using a collection of enhancer-promoter transgenic lines to suppress or enhance the degeneration produced by overexpression of Ppt1 in the adult visual system. Modifier genes identified in our screen connect Ppt1 function to synaptic vesicle cycling, endo-lysosomal trafficking, synaptic development, and activity-dependent remodeling of the synapse. Furthermore, several homologs of the modifying genes are known to be regulated by palmitoylation in other systems and may be in vivo substrates for Ppt1. Our results complement recent work on mouse Ppt1(-/-) cells that shows a reduction in synaptic vesicle pools in primary neuronal cultures and defects in endosomal trafficking in human fibroblasts. The pathways and processes implicated by our modifier loci shed light on the normal cellular function of Ppt1. A greater understanding of Ppt1 function in these cellular processes will provide valuable insight into the molecular etiology of the neuronal dysfunction underlying the disease. FAU - Buff, Haley AU - Buff H AD - Department of Biology, The College of Charleston, Charleston, South Carolina 29424, USA. FAU - Smith, Alexis C AU - Smith AC FAU - Korey, Christopher A AU - Korey CA LA - eng GR - P20 RR016461/RR/NCRR NIH HHS/United States GR - R15 HD052362/HD/NICHD NIH HHS/United States GR - P20-RR16461/RR/NCRR NIH HHS/United States GR - R15-HD052362/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20070403 PL - United States TA - Genetics JT - Genetics JID - 0374636 RN - 0 (Drosophila Proteins) RN - 0 (Membrane Proteins) RN - 0 (Ubiquitin) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (Ppt1 protein, Drosophila) SB - IM MH - Animals MH - Biological Transport MH - Cell Adhesion MH - Drosophila Proteins/*metabolism MH - Drosophila melanogaster/cytology/*enzymology/ultrastructure MH - Endocytosis MH - Endosomes/metabolism MH - Eye/ultrastructure MH - Genes, Dominant MH - Membrane Proteins/*metabolism MH - Models, Biological MH - Nerve Degeneration/*enzymology MH - Signal Transduction MH - Thiolester Hydrolases MH - Ubiquitin/metabolism PMC - PMC1893024 EDAT- 2007/04/06 09:00 MHDA- 2007/09/14 09:00 PMCR- 2007/08/01 CRDT- 2007/04/06 09:00 PHST- 2007/04/06 09:00 [pubmed] PHST- 2007/09/14 09:00 [medline] PHST- 2007/04/06 09:00 [entrez] PHST- 2007/08/01 00:00 [pmc-release] AID - genetics.106.067983 [pii] AID - gen1761209 [pii] AID - 10.1534/genetics.106.067983 [doi] PST - ppublish SO - Genetics. 2007 May;176(1):209-20. doi: 10.1534/genetics.106.067983. Epub 2007 Apr 3.