RohlyA072009T.pdf (2.39 MB)
Role of Membrane Tubulation in NPC1-Mediated Cholesterol Efflux
thesis
posted on 2009-07-22, 00:00 authored by Amy RohlyNiemann Pick Disease Type C (NPC) is an autosomal recessive disorder characterized by abnormal lipid trafficking and storage. The majority of NPC cases are caused by mutations in the NPC1 protein, a multi-pass transmembrane protein found primarily in late endosomes and lysosomes. Preliminary studies have shown that wild type NPC1 localizes to tubulovesicular membranes (TVMs) that move rapidly between membrane compartments, whereas NPC1-I1061T mutant localizes primarily to immobile spherical vesicles. Observations from these experiments support the hypothesis that cholesterol transport is achieved through membrane tubulation and exchange. In order to determine the role of TVMs in cholesterol transport, TVM-associated proteins including EHD1 and Rabs7-9 were investigated in NPC1 TVMs through transfection of wild type and mutant constructs and immunoprecipitation studies. In addition, cholesterol localization was assessed in relation to NPC1 and Rab8 TVMs. Results indicate that EHD1, Rab8, and Rab9 are necessary for NPC1 TVM formation and cholesterol was present in Rab8 TVMs. This data suggests that NPC1, EHD1, and Rabs are essential components in initiating membrane tubulation to facilitate cholesterol transport.
History
Date Modified
2017-06-05Research Director(s)
Kevin T. VaughanCommittee Members
Robert Schulz David HydeDegree
- Master of Science
Degree Level
- Master's Thesis
Language
- English
Alternate Identifier
etd-07222009-111733Publisher
University of Notre DameProgram Name
- Biological Sciences
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