Mechanisms and prevention of protein aggregation
<p>The deposition of amyloid in the central nervous system is associated with prevalent neurological disorders such as Alzheimer's and Parkinson's disease. This thesis studies the mechanisms and prevention of amyloid formation in vitro. We specifically focus on Parkinson's dis...
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| Format: | Thesis |
| Language: | English |
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2016
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| _version_ | 1797082347232821248 |
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| author | Barber, M |
| author2 | Gilbert, R |
| author_facet | Gilbert, R Barber, M |
| author_sort | Barber, M |
| collection | OXFORD |
| description | <p>The deposition of amyloid in the central nervous system is associated with prevalent neurological disorders such as Alzheimer's and Parkinson's disease. This thesis studies the mechanisms and prevention of amyloid formation in vitro. We specifically focus on Parkinson's disease associated α-synuclein (α-syn). Using novel labeling methods we introduce NMR observable labels onto lysosomal protein glucocerebrosidase (GCase), a leading cause of Parkinson's disease. By introducing NMR active labels we are able to study GCase dynamics and screen potential drug therapeutics (chapter 3). Furthermore, we analyze the three way interaction between GCase, α-syn and lipids. We conclude that GCase is able to effectively chaperone α-syn under lysosomal conditions, both preventing amyloidogenesis and destabilizing mature amyloid fibrils (chapter 4). Additionally, a model chaperone-aggregate system is investigated to gain insight into the mechanisms of small heat shock protein chaperoning, and how such mechanisms prevent aggregation (chapter 5). Finally, a high resolution crystal structure of RNA editing enzyme Cid1 is presented, whilst not directly linked to aggregation, many of the techniques used in this thesis were first developed on Cid1 (chapter 7). Together, we utilize NMR, X-ray crystallography, electron microscopy and native mass spectrometry to elucidate aspects of protein aggregation mechanisms and prevention.</p> |
| first_indexed | 2024-03-07T01:26:53Z |
| format | Thesis |
| id | oxford-uuid:924a4f23-a2d3-49af-b201-f29295bdf442 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:26:53Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:924a4f23-a2d3-49af-b201-f29295bdf4422022-03-26T23:24:24ZMechanisms and prevention of protein aggregationThesishttp://purl.org/coar/resource_type/c_db06uuid:924a4f23-a2d3-49af-b201-f29295bdf442BiophysicsGlucocerebrosidaseNuclear Magnetic ResonanceParkinson's diseaseAmyloidEnglishORA Deposit2016Barber, MGilbert, RBaldwin, A<p>The deposition of amyloid in the central nervous system is associated with prevalent neurological disorders such as Alzheimer's and Parkinson's disease. This thesis studies the mechanisms and prevention of amyloid formation in vitro. We specifically focus on Parkinson's disease associated α-synuclein (α-syn). Using novel labeling methods we introduce NMR observable labels onto lysosomal protein glucocerebrosidase (GCase), a leading cause of Parkinson's disease. By introducing NMR active labels we are able to study GCase dynamics and screen potential drug therapeutics (chapter 3). Furthermore, we analyze the three way interaction between GCase, α-syn and lipids. We conclude that GCase is able to effectively chaperone α-syn under lysosomal conditions, both preventing amyloidogenesis and destabilizing mature amyloid fibrils (chapter 4). Additionally, a model chaperone-aggregate system is investigated to gain insight into the mechanisms of small heat shock protein chaperoning, and how such mechanisms prevent aggregation (chapter 5). Finally, a high resolution crystal structure of RNA editing enzyme Cid1 is presented, whilst not directly linked to aggregation, many of the techniques used in this thesis were first developed on Cid1 (chapter 7). Together, we utilize NMR, X-ray crystallography, electron microscopy and native mass spectrometry to elucidate aspects of protein aggregation mechanisms and prevention.</p> |
| spellingShingle | Biophysics Glucocerebrosidase Nuclear Magnetic Resonance Parkinson's disease Amyloid Barber, M Mechanisms and prevention of protein aggregation |
| title | Mechanisms and prevention of protein aggregation |
| title_full | Mechanisms and prevention of protein aggregation |
| title_fullStr | Mechanisms and prevention of protein aggregation |
| title_full_unstemmed | Mechanisms and prevention of protein aggregation |
| title_short | Mechanisms and prevention of protein aggregation |
| title_sort | mechanisms and prevention of protein aggregation |
| topic | Biophysics Glucocerebrosidase Nuclear Magnetic Resonance Parkinson's disease Amyloid |
| work_keys_str_mv | AT barberm mechanismsandpreventionofproteinaggregation |