# Deubiquitinase USP11 in tau regulation and age-related tauopathy

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $373,750

## Abstract

The microtubule-associated protein tau (MAPT) aggregates and accumulates in multiple
neurodegenerative diseases, including Alzheimer’s disease (AD). Abnormal tau accumulation leads to
oligomerization and formation of neurofibrillary tangles associated with neuronal loss, synaptic
dysfunction, and cognitive impairments. While tau undergoes different post-translational modifications
including phosphorylation, acetylation, and ubiquitination, ubiquitination is critical for tau turnover via the
ubiquitin-proteasome system and autophagy-lysosome pathways. Tau is known to be ubiquitinated by
various E3 ligases, including CHIP, TRAF6, and MARCH7. However, very little is known about the role
of deubiquitinases (DUBs) in the regulation of tau function, turnover, or tauopathy. The human
genome encodes >90 DUBs. Ubiquitin specific peptidases (USPs) are the largest family of DUBs
comprising ~50 members in humans. Of these, 27 are expressed in the CNS. Our results from an
unbiased screen of CNS-expressed DUBs identified USP11 and USP13 as positive regulators of tau.
By taking advantage of mouse models and human postmortem tissues together with molecular, cell
biological, imaging, biochemical, electrophysiological, behavioral, viral, histochemical, and recombinant
protein toolsets, this proposal will 1. validate the role of USP11 in tau pathogenesis as a function of age
and sex in vivo, and 2. determine the mechanistic basis of USP11 in tau stability, aggregation, and
toxicity in genetically modified neurons and in vitro systems.
Successful conclusion of these studies will determine the significant contribution of USP11, and its DUB
activity, to tauopathy in humans and mice as a function of aging and sex. USP11 levels could in part
account for potential sex differences in severity of tauopathy in humans and mice. Moreover, these results
will provide novel mechanistic insights to USP11 DUB activity, in concert with RanBP9, in tau modification
and toxicity.

## Key facts

- **NIH application ID:** 9997199
- **Project number:** 1R01AG067741-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** David E Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997199

## Citation

> US National Institutes of Health, RePORTER application 9997199, Deubiquitinase USP11 in tau regulation and age-related tauopathy (1R01AG067741-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997199. Licensed CC0.

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