# Yeast as a gateway to conquering protein misfolding diseases.

> **NIH NIH R35** · UNIVERSITY OF NEVADA RENO · 2021 · $147,771

## Abstract

Abstract of the Funded Parent Grant.
Certain proteins misfold to form self-seeding prion-like aggregates associated with disease. We focus on one
such protein, TDP-43, because it is the major protein associated neuronal aggregates in several
neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and LATE.
LATE is a recently described prevalent TDP-43 proteinopathy that causes dementia that is often misdiagnosed
as Alzheimer’s disease (AD). In addition, TDP-43 is found in aggregates associated with AD and Parkinson’s.
Since TDP-43 forms aggregates and is toxic (inhibits growth) in yeast, a powerful approach to find therapeutic
targets has been to identify yeast genes that modify TDP-43 toxicity. The relevance of the yeast model to
human disease is clear because several yeast genes that modify toxicity of human misfolding disease proteins,
including TDP-43, are homologs of new or known human disease risk factors. We will continue to study the
genesis and toxicity of TDP-43 aggregates in yeast building on our expertise with yeast self-seeding prion
proteins. We expect to learn how TDP-43 causes toxicity in yeast and in what ways this relates to TDP-43
toxicity in flies, primary cortical neurons and mice. One of our goals is to investigate the range of condensates,
oligomers and aggregates formed by TDP-43 and their associated toxicities. Determining which species of
TDP-43 is most toxic is an important step towards understanding of toxicity mechanisms. It is also largely
unknown what cellular functions are targeted by toxic TDP-43 species and the affiliated mechanisms. We will
identify and study cellular targets of toxicity focusing on TDP-43 gain of function toxicity. We will also explore
new models of therapeutic approaches by investigating if overexpression of TDP-43 binding proteins can
inhibit the formation of toxic TDP-43 species, if titration of important proteins by TDP-43 toxic species
contributes to toxicity, and if mutations in TDP-43 can protect WT TDP-43 expressed in the same cell from
forming toxic aggregates. Another gap we seek to address is why TDP-43 is associated with different
diseases. Importantly, as we showed for yeast prions, TDP-43 and other disease proteins can form distinct
aggregate variants (strains), unrelated to mutation, that are associated with distinct characteristics. Thus,
different variants of TDP-43 could affect neuronal types differently causing e.g. ALS vs. LATE. TDP-43 variants
established in yeast would be important tools to identify disease specific variants and facilitate development of
variant specific treatments. We will also investigate the idea that entry into liquid-like granules is an upstream
trigger for toxic species formation to learn if liquid-like granules are therapeutic targets. We will quantify the
relationship between entry of prion proteins into liquid condensates and stochastic formation of prions in yeast.
We will also explore the new area of dis...

## Key facts

- **NIH application ID:** 10396270
- **Project number:** 3R35GM136229-02S1
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** SUSAN W LIEBMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $147,771
- **Award type:** 3
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396270

## Citation

> US National Institutes of Health, RePORTER application 10396270, Yeast as a gateway to conquering protein misfolding diseases. (3R35GM136229-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10396270. Licensed CC0.

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