This proposal aims to delineate the molecular and cellular neurobiology of the human neurodegenerative disorder, Niemann-Pick disease type C (NPC). NPC and its animal model, the cholesterol storage disorder (csd) mouse have been mapped to the pericentomeric region of chromosome 18, although the defective gene has not yet been identified. Two additional neurological mouse mutants, the ataxic (ax) and twirler (tw) are closely linked to the csd locus. A salient feature of NPC and csd is the abnormal accumulation of lysosomal cholesterol and other lipids which is associated with an attenuation of the normal homeostatic responses elicited by mammalian cells with lipoprotein uptake (stimulation of cholesterol ester synthesis, suppression of de novo cholesterol synthesis and down-regulation of LDL receptor activity). The investigators have established that processing of the 30 kD cholesterol binding protein, apolipoprotein (apo) D is deficient in cultured csd astrocytes and there is intracellular retention of a novel 46 kD apo D-immunoreactive protein that serves as a biochemical marker of the mutant cells. The investigators propose to determine the identity and role of this novel 46 kD apo D-immunoreactive protein in csd. To further investigate the role of apo D as an intracellular cholesterol transport protein in neural and non-neural cells, the investigators will use state-of-the-art biophysical techniques to investigate apo D-ligand interactions in cell free systems and in single live cells. Since apo D is a member of the lipocalin family of small hydrophobic ligand carrier proteins (examples of which include retinal binding protein, beta-lactoglobulin and odorant binding protein), these studies will provide new information on the structure- function correlates of apo D binding to cholesterol and related ligands as well as provide new insights into the mechanisms of ligand transport by lipocalins in general. The major phenotypic features of NPC and csd mouse reflect neurodegeneration with hypomyelination and a selective loss of cerebellar Purkinje cells. The investigators have established that secretion of the potent mitogen and growth factor, basic fibroblast factor (bFGF) from cultured astrocytes is deficient. This deficiency is associated with a maturational defect of oligodendrocytes in csd brain. Furthermore, expression of protein kinase C (PKC) which has been shown to be crucial for the expression of myelin protein genes during oligodendrocyte development, is restricted in csd brain. The investigators will therefore investigate the role of growth factors especially bFGF, as well as apo D, in oligodendroglial maturation and of PKC in the hypomyelination of csd brain. Finally, upon identification of the human NPC gene, the investigators propose to clone the mouse homolog of human gene in order to establish its relationship to the human mutation and to determine whether tw and ax are caused by a similar genetic defect(s). These studies will provide new insights into the molecular defect of human NPC and its mouse model, csd, as well as lead to a better understanding of the mechanisms of neurodegeneration in these inherited disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS034339-01
Application #
2273537
Study Section
Special Emphasis Panel (ZRG1-NLS-1 (01))
Project Start
1994-12-30
Project End
1998-11-30
Budget Start
1994-12-30
Budget End
1995-11-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
New England Biomedical Research Center
Department
Type
DUNS #
City
Newington
State
CT
Country
United States
Zip Code
06111
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Shin, Yangmee; Kumar, Ujendra; Patel, Yogesh et al. (2003) Differential expression of D2-like dopamine receptors in the kidney of the spontaneously hypertensive rat. J Hypertens 21:199-207
Ong, Wei-Yi; Goh, Eugene Wee-sing; Lu, Xin-Rong et al. (2003) Increase in cholesterol and cholesterol oxidation products, and role of cholesterol oxidation products in kainate-induced neuronal injury. Brain Pathol 13:250-62
Ong, Wei-Yi; Hu, Chang-Yong; Patel, Shutish C (2002) Apolipoprotein D in the Niemann-Pick type C disease mouse brain: an ultrastructural immunocytochemical analysis. J Neurocytol 31:121-9
Patel, Ramesh C; Kumar, Ujendra; Lamb, Don C et al. (2002) Ligand binding to somatostatin receptors induces receptor-specific oligomer formation in live cells. Proc Natl Acad Sci U S A 99:3294-9
Hu, C Y; Ong, W Y; Sundaram, R K et al. (2001) Immunocytochemical localization of apolipoprotein D in oligodendrocyte precursor-like cells, perivascular cells, and pericytes in the human cerebral cortex. J Neurocytol 30:209-18
Ong, W Y; Kumar, U; Switzer, R C et al. (2001) Neurodegeneration in Niemann-Pick type C disease mice. Exp Brain Res 141:218-31
Hu, C Y; Ong, W Y; Patel, S C (2000) Regional distribution of NPC1 protein in monkey brain. J Neurocytol 29:765-73
Watari, H; Blanchette-Mackie, E J; Dwyer, N K et al. (2000) Determinants of NPC1 expression and action: key promoter regions, posttranscriptional control, and the importance of a ""cysteine-rich"" loop. Exp Cell Res 259:247-56
Rocheville, M; Lange, D C; Kumar, U et al. (2000) Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288:154-7

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