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Title: A chemical, structural and biophysical exploration into the nanoscale properties of amyloid fibrils
Author: Beal, David
ISNI:       0000 0004 5923 0724
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2016
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Amyloid structures have been identified as a key pathological marker in a range of conditions such as Alzheimer’s and Parkinson’s disease. A combination of their disease relevance and potential nanomaterial applications has made understanding amyloid formation and the source of its toxicity of great interest. The fragmentation of amyloid fibrils into smaller particles is important for the kinetics of their formation and how they elicit toxicity. This thesis sheds light on how fibrils formed from different proteins fragment, and compares their resistance to mechanical stress, in order to decipher if fibril fragmentation mechanism is fibril dependent or a property shared by amyloid fibrils in general. To accomplish these goals, this thesis is divided into three sections. The first part of this thesis develops methods for recombinant production and purification of Sup35NMC, Sup35NM and α-synuclein proteins. In vitro polymerisation conditions for these proteins and the commercial proteins lysozyme, β-lactoglobulin and insulin B chain has enabled, via AFM imaging methods and MatLab tracing, the calculation of persistence length from far larger populations than has previously been observed. The second part investigates the resistance to mechanical stress of α-synuclein, β-lactoglobulin and lysozyme fibrils using a fragmentation assay, which enables the determination and comparison of the fibrils’ resistance to mechanical stress. This work has demonstrated that polymer rigidity (Lp) is inherently linked to the resistance of the tested amyloid fibrils to mechanical stress. The third part of the thesis successfully implements a chemical labelling strategy using ‘click’ chemistry to allow a modification of fibril functionality. This has been applied to fluorescence labelling strategies and 19F-labelling for novel methods of determining the population size of amyloid fibrils by 19F DOSY NMR.
Supervisor: Xue, Wei-Feng ; Tuite, Mick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science