# Molecular mechanisms of transthyretin amyloidosis

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $456,448

## Abstract

Many debilitating human diseases are associated with the extracellular misfolding and aggregation
of globular proteins to form fibrillar deposits that are rich in β-sheet. There is considerable evidence
that the process is initiated by local unfolding of the native structure to form aggregation-prone
amyloidogenic intermediates. Aggregation then proceeds via nucleation-growth or downhill
polymerization mechanisms. Despite their key role in amyloidogenesis, influencing the kinetic
partitioning between aggregation and refolding pathways, very little is known about the structure of
amyloidogenic intermediates because of their strong propensity to aggregate. The goals of the
present proposal are to apply state-of-the-art NMR methods to elucidate the fundamental molecular
events involved in transthyretin amyloidosis. Transthyretin amyloidosis is associated with numerous
neurodegenerative diseases and cardiomyopathies. Misfolding and aggregation of transthyretin
leads to fibrous deposits in the peripheral nerves and heart. Deposition of wild type protein is age
related, whereas the familial diseases associated with genetic mutations that destabilize the
quaternary and/or tertiary structure are early onset. The proposed research will provide novel
insights into the fundamental molecular mechanisms by which wild type transthyretin aggregates
and by which familial mutations destabilize the native transthyretin tetramer and drive the
aggregation cascade. Real-time 19F NMR will be used to map the kinetic aggregation landscape of
wild type and pathogenic variant transthyretin, characterize and quantify the population of
intermediates that accumulate on the aggregation pathway, and examine mechanisms of inhibition
by small molecules and peptides. Multidimensional NMR experiments will be utilized to elucidate
the structure and dynamics of an alternate conformational state that promotes tetramer dissociation,
and of cytotoxic monomeric and oligomeric intermediates, formed on the aggregation pathway, that
promote aggregation and fibril growth. This research will advance our understanding of the
underlying molecular events that initiate tetramer dissociation and promote entry into and
progression down the aggregation cascade that leads to amyloid formation by both wild type human
transthyretin and pathogenic variants.

## Key facts

- **NIH application ID:** 10115719
- **Project number:** 5R01DK124211-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PETER Edwin WRIGHT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,448
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115719

## Citation

> US National Institutes of Health, RePORTER application 10115719, Molecular mechanisms of transthyretin amyloidosis (5R01DK124211-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115719. Licensed CC0.

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