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Structural and biophysical studies of α-Synuclein

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TitleInfo
Title
Structural and biophysical studies of α-Synuclein
SubTitle
molecular insights into aggregation in Parkinson's disease
Name (type = personal)
NamePart (type = family)
Kang
NamePart (type = given)
Lijuan
DisplayForm
Lijuan Kang
Role
RoleTerm (authority = RULIB)
author
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Baum
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Jean
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Jean Baum
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Advisory Committee
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chair
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Levy
NamePart (type = given)
Ronald
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Ronald Levy
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Advisory Committee
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RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Kalodimos
NamePart (type = given)
Charalampos
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Charalampos Kalodimos
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Mouradian
NamePart (type = given)
Mary M.
DisplayForm
Mary M. Mouradian
Affiliation
Advisory Committee
Role
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outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
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school
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Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2012
DateOther (qualifier = exact); (type = degree)
2012-10
CopyrightDate (qualifier = exact)
2012
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Subject (authority = RUETD)
Topic
Chemistry and Chemical Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_4299
PhysicalDescription
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electronic resource
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application/pdf
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text/xml
Extent
xiii, 174 p. : ill.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Lijuan Kang
Subject (authority = ETD-LCSH)
Topic
Parkinson's disease--Etiology
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000066839
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3FQ9VBM
Genre (authority = ExL-Esploro)
ETD doctoral
Abstract
α-Synuclein (αsyn), the main component of Lewy Body (LB), is the pathogenesis of Parkinson’s disease (PD) as well as other synucleinopathies. αSyn is intrinsically disordered and its aggregation process is affected by sequence replacement and environment factors. In this dissertation, nuclear magnetic resonance (NMR) was employed to characterize the conformations of αsyn and its variants and Thioflavin T (ThT) fluorescence was utilized to identify aggregation kinetics. The correlation between aggregation kinetics and conformation revealed specific aggregation-prone conformations, thereby providing new insights into the molecular mechanism of αsyn aggregation and possible therapeutic targets for PD.
Investigation of key residues or regions determining the difference of aggregation between human and mouse αsyn reveals that the N terminal substitution A53T plays a key role in controlling the growth rates. The helical propensity of residues 6‒31 and 50‒ 56 also have a good correlation with the aggregation growth rate. The low population of this aggregation-prone conformation in the equilibrium state leads to the proposal of possible selective molecular recognition mechanism for aggregation. The aggregation-prone mutant induces a population shift, which facilitates mutual conformational selection of the favored conformational states and leads to induced-fit structural rearrangement to the formation of stable fibril structures. Further studies on trifluoroethanol (TFE)-induced αsyn aggregation reveal a transient helical intermediate containing the same aggregation-prone region (residues 6‒31) as human-mouse chimera proteins. Finally, the more physiological, acetylated forms of αsyn and A53T familial mutations are investigated. The study is the first identification of conformation and aggregation changes induced by acetylation on αsyn and its familial mutation. The results on the acetylated αsyn and A53T compared with the non-acetylated form confirm that the helical propensity in the particular region (residues 6‒31) is important for fast αsyn aggregation.
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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Kang
GivenName
Lijuan
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2012-09-26 21:34:06
AssociatedEntity
Name
Lijuan Kang
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Name
Author Agreement License
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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.
Copyright
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Copyright protected
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Open
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Permission or license
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