# Investigating autophagic degradation of tau mediated by polyubiquitination

> **NIH NIH R21** · UNIVERSITY OF DELAWARE · 2022 · $423,584

## Abstract

Investigating autophagic degradation of tau mediated by polyubiquitination
 Aberrant degradation and accumulation of tau in human brains is intimately connected to the
development of Alzheimer’s disease (AD). Attentions are now directed to the cellular pathways responsible for
the clearance of tau from neuronal cells, particularly through the autophagy-lysosome pathway. K63-linked
polyubiquitination of tau is intimately involved in the early stage of autophagic degradation of tau. Compared to
the better studied proteasomal degradation of tau, the recognition of tau by the autophagic machinery and the
subsequent degradation by lysosome is poorly understood. Mechanistic details and in-depth biochemical
characterization of the individual players and steps in this process are lacking. How the K63-linked
polyubiquitination of tau mediates its autophagic degradation is largely unknown. Moreover, our understanding
of tau deubiquitination and its role in regulating tau homeostasis is still very limited. We will address these
unanswered questions using K63-polyUb-tau probes generated using a semi-synthetic approach to capture and
identify cognate autophagic receptors and deubiquitinases that are responsible for modulation of the autophagic
degradation of tau. Our findings will unveil new biology in this cellular process and provide potential new targets
for pharmacological intervention of AD.

## Key facts

- **NIH application ID:** 10432378
- **Project number:** 1R21AG077189-01
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Zhihao Zhuang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,584
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432378

## Citation

> US National Institutes of Health, RePORTER application 10432378, Investigating autophagic degradation of tau mediated by polyubiquitination (1R21AG077189-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10432378. Licensed CC0.

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