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Elucidation of The Roles of Metal Ions in Misfolding and Aggregation of TTRwt and TTR-V30M Associated with ATTR Amyloidosis

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July 2024

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2025-07-01

Authors

Burton, Kelley

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East Carolina University

Abstract

Misfolding and aggregation of transthyretin causes a range of diseases, many of which are caused by mutations and destabilization of the protein. Known diseases related to the protein include cardiomyopathy, polyneuropathy, and transthyretin amyloidosis, along with other ailments 1,2,3. The mechanism by which these diseases and many others occur is currently unknown. Through previous studies, metals have been shown to induce aggregation of these proteins in which case it is hypothesized to have an impact on the mechanism’s pathway 4,5. Specifically, Zn2+ ions at significantly higher levels have been observed to induce ex-vivo TTR aggregates in patients affected by amyloidosis compared to those with no current signs of the disease5. The effectiveness of Ca2+ ions in triggering the neurodegenerative process linked to polyneuropathy is crucial in understanding the role of the metal 5. Each of these metals has shown potential possibilities of their specific roles in interactions with transthyretin. Through this study, Zn2+ and Ca2+ ions were used throughout different experiments. WT TTR is a known native form of transthyretin that becomes unstable over time in the structural form1. This protein will be used in comparison with TTR-V30M as it is one of the most common mutations with an association with familial amyloid polyneuropathy (FAP)3. In this thesis, biophysical techniques such as aggregated kinetics, circular dichroism, and isothermal titration calorimetry were used to examine the effects of the metal ion binding. The aim of this study is to investigate the effects of the metal ions on the structure and dynamics of the protein associated with misfolding and aggregation. The biophysical analyses revealed the metal ion bindings induced local structural/ dynamical changes of the protein, promoting misfolding and aggregation.

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