# Validation of a novel tau clearance mechanism.

> **NIH NIH RF1** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $2,157,183

## Abstract

Besides extracellular β-amyloid (Aβ) plaques deposition, Alzheimer’s disease (AD) is pathologically
characterized by intracellular tauopathy that accumulation and aggregation of abnormally hyperphosphorylated
microtubule-associated protein MAPT/tau form neurofibrillary tangle (NFT), resulting in loss of functional
neurons. Although Aβ plaques play a key role in initiating AD pathogenesis, the severity of cognitive decline
correlates best with the burden of neocortical NFTs. Therefore, promoting the clearance of accumulated tau
represents a promising therapeutic strategy for tauopathy patients, which depends on a better understanding of
the mechanisms underlying the degradation of pathological tau species during disease progression. Our
ultimate goal is to elucidate the complex mechanisms underlying how tauopathies, such as AD, initiate and
progress, and to develop effective therapeutic approaches to treat tauopathies. It is reported that tau can be
degraded by autophagy-lysosomal or ubiquitin-proteasomal systems. Tau degradation is closely associated with
its various post-translational modifications, including phosphorylation, acetylation, and ubiquitination. Our
preliminary studies indicate that tau is modified by linear ubiquitin chains in normal mouse brain tissues, which
were substantially decreased in tauopathy mouse models. Linear ubiquitination of tau promotes tau clearance
in an autophagy-dependent manner. We further found that oxidative stress can increase deubiquitinase OTULIN
activity by promoting its phosphorylation, which both are substantially increased in the brain tissues from AD
patients. Inhibition of OTULIN prevented the accumulation of pathological tau species and attenuated its
cytotoxicity in a tauopathy mouse model. Therefore, we hypothesize that linear ubiquitination promotes tau
degradation, which is inhibited by deubiquitinase OTULIN; oxidative stress activates OTULIN, resulting in
increased tau aggregation and neurotoxicity. Pharmacological inhibition of OTULIN may mitigate tauopathy
progression by enhancing the clearance of tau aggregates. Three specific aims are proposed to test this
hypothesis. Aim1 will determine the role of linear ubiquitination in regulating tau accumulation and neuronal
toxicity and investigate the autophagic-lysosomal mechanism. Aim2 will investigate oxidative stress-mediated
mechanisms during OTULIN-induced tauopathies using a systems biology approach. Aim 3 will test a newly
developed OTULIN inhibitor in promoting tau clearance and mitigating its cellular toxicity in tauopathy animal
models. Our studies will have a strong impact by providing: 1) novel mechanisms regulating tau aggregation
and proteotoxicity; 2) new mechanistic link between oxidative stress and tau linear ubiquitination; 3) potential
therapeutic approaches for mitigating tauopathy and cognitive decline, eventually benefiting AD patients.

## Key facts

- **NIH application ID:** 10445826
- **Project number:** 1RF1AG072703-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Kiran Bhaskar
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,157,183
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445826

## Citation

> US National Institutes of Health, RePORTER application 10445826, Validation of a novel tau clearance mechanism. (1RF1AG072703-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445826. Licensed CC0.

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