Author Date

2024-06-21

Degree Name

BS

Department

Chemistry and Biochemistry

College

Physical and Mathematical Sciences

Defense Date

2024-06-18

Publication Date

2024-06-21

First Faculty Advisor

John C Price

First Faculty Reader

Mark K Transtrum

Honors Coordinator

Walter Paxton

Keywords

transthyretin amyloidosis (ATTR), aging, IPSA, protein misfolding, proteomics, amyloid cascade

Abstract

This study attempts to provide the first comprehensive proteomic analysis of protein folding stability (PFS) in transthyretin amyloidosis (ATTR) across different age groups to shed light on the mechanisms of age-mediated protein misfolding and the amyloid cascade. Utilizing the Iodine Protein Stability Assay (IPSA), we characterize the PFS of proteins across the serum proteome in a cohort of 100 individuals (18-85 years old) to investigate the impact of aging on changes in protein folding across the proteome. Presented are preliminary data from 20 participants.

Our study overcomes limitations in previous studies of ATTR by providing a structural perspective on TTR misfolding under physiological conditions and within the context of the entire proteome.

Our findings suggest that aging increases proteolytic activity by reducing the effectiveness of serine protease inhibitors (SPIs) which then encourages TTR cleavage and misfolding, triggering the amyloid cascade. We also identify an unexpected axis of instability in TTR with aging that challenges current models of TTR tetramer collapse. Additionally, we examine the role of protein folding stability (PFS) on protein turnover rates (TR) and amyloid clearance in six individuals and propose a model explaining the role of aging and protein stability in amyloid deposition and clearance.

Our findings showcase the strengths of IPSA for studying PFS across the proteome, particularly in the context of aging and amyloid diseases. We propose that quantifying PFS could serve as a diagnostic tool for proteome health and disease risk, and our approach introduces a new dimension and crucial perspective to studying the pathogenesis and pathophysiology of disease.

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