The long-term objective of this research is to develop Drosophila as a model system for studying the etiology of infantile neuronal ceroid lipofuscinosis (INCL). INCL is one of a group of related neurological diseases collectively known as Batten Disease that primarily affect infants and children. INCL, like all forms of Batten Disease, is a fatal neurodegenerative disease characterized by cytological evidence of abnormal lysosome function. INCL is caused by mutations in the palmitoyl-protein thioesterase gene (PPT1), but the molecular mechanism of neuronal pathogenesis is not known. Novel approaches to the study of INCL will help expedite the discovery of treatments for this devastating disease. The recent sequencing of the Drosophila genome has revealed that flies harbor many homologs of human disease genes, including PPT1. If mutation of Drosophila PPT1 (DmPPT1) were to recapitulate aspects of human INCL, it would provide an opportunity to investigate the etiology of INCL in a model system where extensive genetic and molecular tools are available for investigation. The goal of experiments proposed in this application is to determine if mutation to DmPPT1 in Drosophila causes neurological phenotypes characteristic of human INCL.
The specific aims of the proposal are: 1. Determine the phenotypic consequences of removing DmPPT1 function by gene mutation. 2. Determine the phenotypic consequences of disrupting DmPPT1 function by RNA interference.
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| Hickey, Anthony J; Chotkowski, Heather L; Singh, Navjot et al. (2006) Palmitoyl-protein thioesterase 1 deficiency in Drosophila melanogaster causes accumulation of abnormal storage material and reduced life span. Genetics 172:2379-90 |
| Glaser, Robert L; Hickey, Anthony J; Chotkowski, Heather L et al. (2003) Characterization of Drosophila palmitoyl-protein thioesterase 1. Gene 312:271-9 |
