Niemann-Pick type C (NPC) is an inherited, pediatric neurodegenerative disease thought to be due to the accumulation of unesterified cholesterol in neurons. In the model organism Drosophila, there are two NPCI genes, NPC1a and NPC1b. However, there are no known point mutations in these genes, and consequently, their role in disease or development is not known. The NPC1 proteins have significant homology to the developmental regulator and tumor suppressor morphogen Patched (Ptc).The first hypothesis driving this proposal is that ptc mutant files develop a NPC-like disease. This is based on our following findings: (1) we have isolated an adult specific allele of ptc and these flies show progressive, age-dependent locomotor deficits, (2) the brains from these mutants show neurons with inclusion bodies similar to the inclusions found in neurons of NPC and several other lysosomal storage disorders. The second hypothesis driving this proposal is that the primary cause for the NPC disease-state in ptc flies is not the accumulation of cholesterol in neurons. This is based on our finding that overloading the cholesterol pathway in wild type leads to accumulation of cholesterol and formation of inclusion bodies in neurons; however, these flies do not develop any of the behavioral defects. Similarly, feeding cholesterol to mutant flies does not worsen the disease-state. These are consistent with the previous observation that there is no correlation between the extent of presence of inclusions and the severity of the disease. The third hypothesis driving this proposal is that the NPC1 proteins in Drosophila might regulate developmental processes in conjunction with Ptc. This is based on our observation that some of the developmental defects in ptc mutants are partially penetrant and that the two NPC1 genes are the closest of ptc in flies and might complement the loss of Ptc activity.Thus, our specific aims are: 1) Determine why ptc mutant flies develop the NPC-like disease: the molecular basis, 2) Isolate dNPC1 mutations and determine: a) if loss of function for these genes leads to the NPC disease, b) if the two genes are required for neurogenesis, and c) the relationship between Ptc and NPC1 in disease and development, 3) Perform modifier screens to isolate adult specific mutations in dNPC1 genes. This work will provide insight into the role of these proteins in neurodegenerative diseases and development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Tagle, Danilo A
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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Gazi, Michal; Shyamala, Baragur V; Bhat, Krishna Moorthi (2009) A neurodegenerative disease affecting synaptic connections in Drosophila mutant for the tumor suppressor morphogen Patched. Dev Biol 334:311-23