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Investigation of protein - protein interactions underlying alpha-synuclein aggregation in Parkinson's diseases
Descriptive
TitleInfo
Title
Investigation of protein - protein interactions underlying alpha-synuclein aggregation in Parkinson's diseases
Name
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NamePart
(type = family)
Yang
NamePart
(type = given)
Xue
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(type = date)
1991-
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Xue Yang
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(authority = RULIB)
author
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(type = personal)
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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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Khare
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Sagar
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Sagar Khare
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Advisory Committee
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internal member
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(type = family)
Nieuwkoop
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Andrew
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Andrew Nieuwkoop
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Advisory Committee
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Mouradian
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(type = given)
Maral
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Maral Mouradian
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Advisory Committee
Role
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(authority = RULIB)
outside member
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
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School of Graduate Studies
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school
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Text
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theses
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2020
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2020-01
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2020
Language
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English
Abstract
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Alpha-synuclein (αSynuclein) accumulation and aggregation is related to many neurodegenerative diseases like Alzheimer's diseases, Parkinson’s diseases, and dementia with Lewy bodies. However, the mechanism of αSynuclein aggregation and the relationship between aggregation pathways and toxicity are still unclear. Beta-synuclein (βSynuclein) is a homologue protein of αSynuclein with high sequence similarity but plays a different role in neurodegenerative diseases. βSynuclein has shown anti-Parkinson capacity in mouse models. In this work, we used βSynuclein as a comparison to answer why αSynuclein fibrils are good templates for seeding aggregation and what kind of interactions promote aggregate formation or inhibition. The work in this thesis explores structure, toxicity, dynamic and seeding aggregation capacity of different αSynuclein oligomers and fibrils which provide critical information for therapeutic targets and designs.
By characterizing and comparing αSynuclein, βSynuclein and α/β co-incubated fibrils, we suggest that the stability and dynamics of the fibrils play an important role in controlling the fibril seeding aggregation ability. However, both αSynuclein and βSynuclein fibrils show similar cellular toxicity which suggest that seeding monomer aggregation is not the only contribution for fibril toxicity. Using solution NMR, we show that the initial step for fibril seeding is through interactions at the first 40 residues of the N-terminus. The interactions between αSynuclein stable oligomers and monomers are primarily located at the first 12 residues which results in inhibiting fibril seeding aggregation processes through competing interactions. Coupling these facts together suggests that peptides or small molecular targets that interact with the N-terminus of αSynuclein may be a good approach to inhibit αSynuclein seeding processes and increase the dynamics of fibril packing interfaces can be novel strategies to reduce amyloid toxicity.
By characterizing and comparing αSynuclein, βSynuclein and α/β co-incubated fibrils, we suggest that the stability and dynamics of the fibrils play an important role in controlling the fibril seeding aggregation ability. However, both αSynuclein and βSynuclein fibrils show similar cellular toxicity which suggest that seeding monomer aggregation is not the only contribution for fibril toxicity. Using solution NMR, we show that the initial step for fibril seeding is through interactions at the first 40 residues of the N-terminus. The interactions between αSynuclein stable oligomers and monomers are primarily located at the first 12 residues which results in inhibiting fibril seeding aggregation processes through competing interactions. Coupling these facts together suggests that peptides or small molecular targets that interact with the N-terminus of αSynuclein may be a good approach to inhibit αSynuclein seeding processes and increase the dynamics of fibril packing interfaces can be novel strategies to reduce amyloid toxicity.
Subject
(authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject
(authority = local)
Topic
Aggregation
Subject
(authority = LCSH)
Topic
Synucleins
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_10515
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application/pdf
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text/xml
Extent
1 online resource (xi, 125 pages) : illustrations
Note
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Ph.D.
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Includes bibliographical references
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Title
School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
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doi:10.7282/t3-nqjb-vb61
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Yang
GivenName
Xue
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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2020-01-08 14:32:40
AssociatedEntity
Name
Xue Yang
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Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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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.
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2020-01-31
DateTime
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2022-01-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 30th, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2020-01-09T17:06:35
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2020-01-09T17:06:35
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