# Overcoming proteasome impairment with small molecules

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2022 · $167,891

## Abstract

Other than the recently approved antibody, Aducanumab, which may help early onset patients,
there are no therapeutic treatments to prevent, slow or cure neurodegenerative diseases such
Alzheimer's disease and related dementias (ADRD). Current treatments only temporarily
suppress disease symptoms. This work aims to investigate small molecule 20S proteasome
activation as a new, innovative therapeutic strategy to slow and/or prevent disease progression.
Proteins such as amyloid-Beta, alpha-synuclein and dipeptide repeat units are intrinsically disordered
proteins (IDPs), which have a high tendency to oligomerize and aggregate upon accumulation.
The exact mechanism by which these oligomers induce neurotoxicity is complex and still
debated. However, it is widely accepted that accumulation of these aggregation-prone proteins
results in (1) toxic oligomeric species and (2) proteasome impairment, which are two classic
hallmarks of neurodegenerative disorders that ultimately drive disease progression.
In this exploratory R21 grant, we are pioneering a new paradigm in drug discovery, which is
focused on preventing the accumulation of IDPs by enhancing the activity of the 20S
proteasome using small molecules. Our hypothesis is that small molecule 20S proteasome
enhancement will induce the degradation of IDPs, and thereby prevent and restore proteasome
function, that was impaired by these IDP oligomers. To test this hypothesis, we will explore the
efficacy of two new, but distinct classes of 20S proteasome enhancers, discovered and
published by our research group, for their ability to (1) prevent IDP accumulation and (2) restore
impaired proteasome function.
Impact: According to the National Institutes of Aging, AD is the 6th leading cause of death in the
US, yet it remains mostly without effective treatment options. Successful completion of this work
will validate a new strategy that tackles two fundamental steps in the pathogenesis of these
disorders, which may provide a therapeutic strategy to treat these devastating dementias.

## Key facts

- **NIH application ID:** 10427952
- **Project number:** 1R21AG076994-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** JETZE J. TEPE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $167,891
- **Award type:** 1
- **Project period:** 2022-04-15 → 2024-01-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427952

## Citation

> US National Institutes of Health, RePORTER application 10427952, Overcoming proteasome impairment with small molecules (1R21AG076994-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10427952. Licensed CC0.

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