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Title: Towards the elucidation of pathophysiology of amyloid conversion of globular proteins
Author: Verona, Guglielmo
ISNI:       0000 0004 7661 0227
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Amyloidoses are a group of diseases caused by the conversion of soluble proteins into pathogenic ordered fibrillar aggregates. The mechanism driving in vivo the structural transformation of these proteins has not yet been clearly elucidated. My work has focused on two plasma proteins that make amyloid in vivo starting from precursors deeply different in terms of structure and function: transthyretin (TTR) and the apolipoprotein C-III variant, D25V (D25V apo C-III). Apo C-III is mostly synthesized by the liver and is a major component of HDL. We have described the first variant causing a genetic form of renal amyloidosis. In the work presented here, structural and functional characterization of the newly described D25V apo C-III variant was carried out together with the investigation of its aggregation mechanism, showing a modest loss of function and an increased tendency to aggregate in physiological buffer in the lipid-free state. TTR is mainly synthesized by the liver and the choroid plexus in the CSF and is the main transporter of thyroxine in the CSF and the secondary transporter in plasma. The mechanism of TTR fibrillogenesis has been investigated for decades. Our group has recently proposed a new pathway for TTR amyloidogenis mediated by selective tryptic cleavage, in alternative to the commonly accepted low pH induced aggregation mechanism. Further characterization of the mechanism, including the identification of the culprit protease responsible for proteolytic cleavage in vivo was carried out showing a correlation between TTR stability and susceptibility to proteolysis. The inhibitory activity of stabilisers and their effect on protein structure and dynamics were also studied using a combination of spectroscopic techniques including NMR. The identification of the enzyme responsible for cleavage in vivo, opens up a completely new scenario for understanding the mechanism and the history of the disease in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available