# Inhibiting fibrillation of Tau through changes in local intramolecular interactions

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $37,674

## Abstract

Project Summary/Abstract
Neurodegenerative diseases such as Alzheimer's disease are characterized by the abnormal deposition of
fibrillar aggregates in the brain. The microtubule-associated protein tau can form such assemblies and defines
a diverse group of diseases termed tauopathies. The prevalence of tau fibrils strongly correlates with disease
progression, with mutations that increase aggregation propensity directly linked to disease. Even so, tau is
thermostable and does not form fibrils in vitro or in cells without specific inducers. The intrinsically disordered
nature of tau protein allows the sampling of multivalent interactions, facilitating the biological activity of
microtubule binding. However, there is a gap in knowledge of how tau structurally transitions from aggregation-
resistant to an aggregation-prone conformation. This proposal aims to fill this gap in knowledge by studying local
interactions involving amyloid motifs in the aggregation-prone repeat domain of tau. I will leverage the differences
in fibril toxicity of two isoforms of tau to create a map of sequence properties that define the fibrillization properties
of tau. I hypothesize that interactions between amyloid motifs and their surrounding sequence mediate tau
aggregation propensity; therefore, stabilizing these interactions to form local structures can prevent fibril
formation. In this proposal, I will identify atomic interactions in tau that modulate aggregation propensity using
molecular dynamics simulations combined with peptide aggregation assay. Then I will engineer modified tau
constructs that are predicted to stabilize the local structure. Lastly, I will determine the local structure of the
stabilized tau species using cross-linking mass spectrometry. Then I will test whether the stabilized structure
maintains flexibility in the microtubule-binding motifs through in vitro and in cell microtubule-binding assays. This
integrative approach will create a map of stabilizing local interactions within a tau monomer to design
aggregation-resistant conformations of tau that retain biological microtubule-binding activity. By understanding
the biophysical basis behind early misfolding events in tau, this project can inform the future design of diagnostics
and therapeutics that stabilize non-toxic tau species to treat the diverse family of tauopathies.

## Key facts

- **NIH application ID:** 10463883
- **Project number:** 1F31NS127513-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Sofia Bali
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,674
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463883

## Citation

> US National Institutes of Health, RePORTER application 10463883, Inhibiting fibrillation of Tau through changes in local intramolecular interactions (1F31NS127513-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10463883. Licensed CC0.

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