# Direct Proteasome Impairment by Neurotoxic Tau Oligomers

> **NIH NIH F31** · WEST VIRGINIA UNIVERSITY · 2020 · $45,520

## Abstract

ABSTRACT
Virtually all neurodegenerative diseases are characterized by the accumulation of proteins that are thought
to play a significant role in disease pathogenesis. One of the cell’s primary systems for the removal and
degradation of misfolded or damaged proteins is the Ubiquitin Proteasome System (UPS). However,
numerous studies have shown significant impairment of the UPS in essentially all of these neurodegenerative
diseases. What is not known is why protein degradation is impaired, allowing misfolded proteins to accumulate
and become toxic in these diseases, or if the stimulation of the proteasome function could be a viable
treatment. All of these diseases are characterized by their own unique protein deposits. However, the
microtubule associated protein tau is unique in that it is ubiquitously implicated in most neurodegenerative
diseases as the secondary protein involved in these protein deposits. The preliminary data that we have
gathered led us to the central hypothesis that tau oligomers bind to the 20S proteasome, and inhibit protein
degradation by stabilizing the closed gate conformation. The first aim in this proposal is to determine the
molecular mechanism by which soluble tau oligomers impair the proteasome. This will allow us to identify and
understand at a molecular level, a general mechanism of toxicity that could be common to many
neurodegenerative diseases. The second aim in this proposal is to determine the feasibility of increasing
proteasome activity to reduce toxicity due to the presence of specific oligomers in neuronal cell models. The
proposal is expected to have an important and positive impact because it will allow us to identify and
understand, at a molecular level, a general mechanism of toxicity in Alzheimer’s disease that could be
common to many neurodegenerative diseases; and furthermore, it will assess the feasibility of reversing this
toxicity to potentially treat neurodegenerative diseases.

## Key facts

- **NIH application ID:** 9830534
- **Project number:** 5F31AG058473-03
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Raymond Theodore Anderson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2017-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830534

## Citation

> US National Institutes of Health, RePORTER application 9830534, Direct Proteasome Impairment by Neurotoxic Tau Oligomers (5F31AG058473-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830534. Licensed CC0.

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