The broad, long-term objective of this proposal is to utilize the genetically tractable model organism, S. cerevisiae, to study the cellular function of the Niemann-Pick disease type C (NP-C) protein, NPC1. NP-C is a fatal neurodegenerative disorder with a prevalence of 1 in 150,000 live births. Biochemically, NP-C is a lipid storage disorder marked by the lysosomal accumulation of unesterified cholesterol. The recent cloning of the NPC1 and NPC2/HEJ genes, which are causative in NP-C disease, established the molecular basis for NP-C, but the functions of the NPC proteins have yet to be determined.
The specific aims of this proposal will test the feasibility of using S. cerevisiae as a model system to study NPC1 function.
The specific aims are: 1) to test the hypothesis that the S. cerevisiae homolog of NPC 1, NCR 1, is required for retrograde transport from the vacuole; and 2) to determine whether S. cerevisiae can be used as a model system to assess the functional consequences of patient mutations in the NPC1 gene. We will utilize fluorescently labeled lipids to test whether yeast cells lacking the NCR1 protein are defective in retrograde transport from the vacuole. To examine the functional consequences of patient mutations in NPC1, we will take advantage of a growth phenotype we have identified in yeast that lack a functional NCR1/NPC1 protein to assay for functional complementation. The health relatedness of this project is the establishment of a basis and possible future diagnostic tool for Niemann Pick disease type C.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS044743-03
Application #
6764002
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Tagle, Danilo A
Project Start
2002-08-01
Project End
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$35,490
Indirect Cost
Name
Emory University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Berger, Adam C; Salazar, Gloria; Styers, Melanie L et al. (2007) The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3. J Cell Sci 120:3640-52
Berger, Adam C; Vanderford, Thomas H; Gernert, Kim M et al. (2005) Saccharomyces cerevisiae Npc2p is a functionally conserved homologue of the human Niemann-Pick disease type C 2 protein, hNPC2. Eukaryot Cell 4:1851-62
Baldwin, E L; Berger, A C; Corbett, A H et al. (2005) Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II. Nucleic Acids Res 33:1021-30