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Cholesterol trafficking and the etiology of NPC disease.

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Call No.	QP752.C5 R45 2003
Author	Reid, Patrick C.
Title	Cholesterol trafficking and the etiology of NPC disease.
Date	2003
Abstract	Niemann-Pick type C (NPC) disease is a fatal autosomal recessive pediatric neurovisceral disorder characterized clinically by progressive neurodegeneration in the central nervous system (CNS) and hepatosplenomegaly. Biochemically, it is characterized by the intracellular accumulation of unesterified cholesterol, gangliosides, and other lipids within the endosomal/lysosomal system in cells of the liver, spleen, and CNS. The majority (95%) of NPC disease cases are due to mutations within the Npc1 gene. This gene encodes a 13-pass transmembrane protein localized to late-endosomes, and believed to function in the vesicular sorting of both membrane lipids and fluid phase constituents from late endosomes to various destinations. The mechanism by which a deficiency in the NPC1 protein manifests into the etiology of NPC disease remains unknown. This thesis provides evidence for the critical link between endogenous cholesterol trafficking events and the etiology of NPC disease. Defects in the trafficking of LDL-derived cholesterol in NPC deficient cells had been previously established. Work in this thesis provides evidence that endogenously synthesized cholesterol trafficking events are also defective in NPC1 disease. The extent of this defect is cell type dependent, and appears to be related to the cholesterol trafficking dynamics within the individual cell type. The accumulation of cholesterol within neurons of the CNS in NPC disease is controversial. Utilizing a powerful new method to detect cholesterol, at a level previously undetectable, this thesis illustrates that cholesterol does accumulate within various neuronal populations. Accumulation occurs before any signs of neurodegeneration or neuronal cell loss are detectable, and well before the clinical manifestations of the disease occur. In addition, cholesterol not only accumulates within the neuronal perikarya of Purkinje neurons, but also within their extensive dendritic network, providing the first plausible explanation for why the progressive loss of Purkinje neurons is a hallmark of NPC disease. Next, this thesis describes the selection and characterization of a new CHO cell mutant defective in cholesterol-lipid raft organization, from which we hope to identify novel proteins associated with lipid raft membrane organization. Finally, preliminary evidence for a novel-recycling pathway for endogenously synthesized cholesterol between intracellular organelles and the plasma membrane is described.
Description	1 online resource (xiv, 197 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Chang, Ta Yuan ; Hickey, William F. ; Barchowsky, Aaron ; Harwood, H. James, Jr.
Subject	Cholesterol -- Physiological transport. ; Cholesterol -- Genetic aspects. ; Purkinje cells. ; Neurogenetics. ; Neimann-Pick Diseases -- etiology.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.3348

Title	reid2003 1
Full Text	Cholesterol Trafficking and the Etiology of NPC Disease A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Patrick C. Reid DARTMOUTH COLLEGE Hanover, New Hampshire August 7, 2003

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Cholesterol trafficking and the etiology of NPC disease.

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Cholesterol trafficking and the etiology of NPC disease.

Cholesterol trafficking and the etiology of NPC disease.