# The Role of Ubiquitination in Tau Oligomers Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $748,330

## Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder imposing an unbearable socio-
economic burden worldwide. Current therapeutic approaches fail to halt AD progression, indicating the need for
new strategies, which is the focus of this project. Neurofibrillary tangles (NFTs)–the major pathological hallmark
in human AD and related tauopathies, occurs when microtubule-associated protein tau (MAPT or tau) forms
aggregates. Further, accumulation of the tau aggregates in AD brain promotes cognitive decline, accompanied
with dysregulated proteostasis in neurons. However, we and others have previously shown that smaller soluble
tau-aggregates, called oligomers, are the most toxic species and form prior to NFTs in human AD. Our
preliminary studies show that AD-brain-derived tau oligomers (BDTOs) exhibit unique post-translational
modifications (PTMs), including specific ubiquitin-linkages, which seem to be involved in tau-aggregation that
influence stability, propagation in a prion-like manner and subsequent cognitive decline. Understanding the
fundamental signature ubiquitination pattern by which tau oligomers evade proteasomal degradation and
promote its assembly, stability, secretion and propagation is important for developing disease-modifying
therapies for AD.
This proposal will test the central hypothesis that the unique mono-ubiquitination of tau oligomers facilitate to
evade the neuronal ubiquitin-proteasome system (UPS), and promote its accumulation in neurons, which
causes synaptic dysfunction. Furthermore, these tau oligomers contribute to increased neuronal toxicity,
secretion and propagation of a prion-like tau pathology, and also promote neuroinflammation by modulating
microglia and astrocytes activation. In specific aim 1, using mass-spectroscopy and site-directed mutagenesis,
we will define the mechanism and functional impact of lysine modification, and particularly reversible mono-
ubiquitination, in regulating the processing, assembly and trafficking of tau oligomers in neurons. This will also
define the biochemical and structural consequences of tau oligomer mono-ubiquitination in modulating the
efficacy of tau oligomer assembly, secretion and propagation in AD, which will serve as a potential AD
antemortem biomarker, and provide key information for targeting the pathological tau. Using isotope labeling by
amino acids in vitro and in vivo (SILAC) proteomics approaches, in specific aim 2, we will define the mechanism
by which mono-ubiquitination controls the interplay between PHF-tau assembly and tau oligomers secretion and
propagation in primary neurons. Further, physiological mechanisms for regulation of tau-deubiquitination and AD
pathogenesis will be verified using complementary approaches. In specific aim 3, we will investigate the role of
deubiquitinase Otub1 on tau oligomer accumulation, trafficking and self-propagation in neurons.

## Key facts

- **NIH application ID:** 10812331
- **Project number:** 5R01AG077253-03
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Rakez Kayed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $748,330
- **Award type:** 5
- **Project period:** 2022-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812331

## Citation

> US National Institutes of Health, RePORTER application 10812331, The Role of Ubiquitination in Tau Oligomers Pathogenesis (5R01AG077253-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10812331. Licensed CC0.

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