# A synthetic biology approach for tau post-translational modifications in AD

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2023 · $651,090

## Abstract

Oligomeric forms of tau are the primary source of neurotoxicity in a wide range of neurodegenerative diseases.
Structural studies of pathological tau aggregates isolated from tauopathy patient brains have uncovered a
diversity of disease-specific tau conformations and structural polymorphs, but the mechanism for how they
misfold into pathogenic species remains unknown. Here we aim to test a long-standing hypothesis that post-
translational modifications (PTMs), such as phosphorylation and acetylation at disease-associated sites, mediate
tau oligomerization, structural polymorph-dependent propagation, and neurotoxicity. We propose a bottom-up
approach for directly assessing the impact of pre-defined, disease-associated phosphorylation and acetylation
of full-length human tau. For the first time, we demonstrate that a state-of-the-art synthetic biology approach
enables the production of recombinant site-specifically phosphorylated tau (rp-tau), and that rp-tau with a single
modification is sufficient to adopt pathological conformations. This new capability will be expanded to include
site-specific lysine acetylation of tau to produce full-length tau with defined PTMs (including simultaneous
phospho- and acetyl-) implicated in Alzheimer’s disease (AD) and AD-related dementias (ADRD). The new
reagents developed here will be used to determine the impact of site-specific tau PTMs on tau conformation
using cryo-EM, microtubule binding, oligomerization, neurotoxicity, and tau seeding. We will generate
monoclonal antibodies against tau with defined PTMs and AD/ADRD relevant conformations validated through
cryo-EM. The impact of the project will be to provide transferrable resources to test tau PTMs with unprecedented
resolution and uncover the molecular signature and mechanisms that mediate tau oligomerization,
conformational change, and seeding.

## Key facts

- **NIH application ID:** 10739891
- **Project number:** 1R01AG083876-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Yongku Peter Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $651,090
- **Award type:** 1
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739891

## Citation

> US National Institutes of Health, RePORTER application 10739891, A synthetic biology approach for tau post-translational modifications in AD (1R01AG083876-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10739891. Licensed CC0.

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