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The relationship between Niemann Pick type C2 protein and lysobisphosphatidic acid in cholesterol transport

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TitleInfo
Title
The relationship between Niemann Pick type C2 protein and lysobisphosphatidic acid in cholesterol transport
Name (type = personal)
NamePart (type = family)
Jochum
NamePart (type = given)
Annette Marie
NamePart (type = date)
1991-
DisplayForm
Annette Marie Jochum
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Storch
NamePart (type = given)
Judith
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Judith Storch
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Advisory Committee
Role
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chair
Name (type = personal)
NamePart (type = family)
Brasaemle
NamePart (type = given)
Dawn
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Dawn Brasaemle
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Dixon
NamePart (type = given)
Joseph
DisplayForm
Joseph Dixon
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2016
DateOther (qualifier = exact); (type = degree)
2016-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2016
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Niemann Pick Type C (NPC) disease is caused by a mutation in either Niemann Pick C1 or C2 protein, both found in the lysosome and both involved in the export of cholesterol from the lysosome to other parts of the cell. NPC2 has been shown to interact directly with membranes to extract and transport cholesterol while minimizing its exposure to the aqueous environment, but defective NPC2 causes cholesterol accumulation within the lysosome. NPC2 has also been shown to be able to interact with more than one membrane at once. In particular, it appears as though NPC2 has a distinct and specific interaction with the unique lysosomal phospholipid lysobisphosphatidic acid (LBPA), which augments wild type (WT) NPC2 function dramatically. In this study, alanine point mutations in the “hydrophobic knob” region of NPC2, which is proposed to interact with membranes directly, reveal new information about the structure-function relationship of NPC2. Only some of the mutant NPC2 proteins respond to the inclusion of LBPA in membranes, reinforcing that this region is LBPA-sensitive. Past studies have shown that phosphatidylglycerol (PG) is a precursor to LBPA, which is generated along the lysosomal pathway and retains its precursor’s fatty acid composition and glycerol backbone orientation. It has been demonstrated that an increase in lysosomal LBPA content can increase cholesterol efflux from the lysosomes and relieve some of the phenotypical cholesterol accumulation in npc1-/- fibroblasts. We reasoned that because of the interaction between LBPA and NPC2, increasing lysosomal LBPA content in npc2-/- cells would not clear cholesterol from the LE/LY. Thus, WT, npc1-/-, and npc2-/- fibroblasts were supplemented with PG liposomes, which increased cellular LBPA content by at least 2-fold. The increase in LBPA relieved cholesterol accumulation in NPC1 fibroblasts significantly, in agreement with previous literature, but did not diminish cholesterol distribution in NPC2-deficient fibroblasts. This reinforces the critical interaction of NPC2 with LBPA in cholesterol trafficking. In addition, the studies suggest that LBPA supplementation may have therapeutic benefits in patients with mutated NPC1, which account for 95% of NPC cases, but not in patients with defective NPC2.
Subject (authority = RUETD)
Topic
Nutritional Sciences
Subject (authority = ETD-LCSH)
Topic
Niemann-Pick diseases
Subject (authority = ETD-LCSH)
Topic
Lysosomes
RelatedItem (type = host)
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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ETD_7420
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electronic resource
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application/pdf
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text/xml
Note
Supplementary File: Figure 1.2 with proper citation
Extent
1 online resource (xii, 111 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Annette Marie Jochum
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3N58PP0
Genre (authority = ExL-Esploro)
ETD graduate
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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Jochum
GivenName
Annette
MiddleName
Marie
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-06-06 17:29:49
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Name
Annette Jochum
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Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2018-10-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2018.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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