# Using naturally-occurring fungal prions as models of neurodegenerative protein misfolding

> **NIH NIH R35** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2020 · $315,257

## Abstract

PROJECT SUMMARY
Neurodegenerative disease is a general term to collectively describe the numerous disorders that affect neurons
of the brain and spinal cord. These diseases primarily manifest as dementias (mental disorders such as
Alzheimer's disease) or ataxias (movement disorders such as amyotrophic lateral sclerosis), and are notorious
for their lack of effective treatments. The direct cost to Americans for treating Alzheimer's disease alone is
predicted to exceed $1 trillion in the year 2050. This does not include the emotional burden or the unpaid care
provided by family members.
A common feature of most age-onset neurodegenerative diseases is the accumulation of specific proteins into
large aggregates within neuronal cells and tissues. Diseases are frequently characterized by which particular
proteins are misfolding and aggregating. In many cases, these proteins form amyloid-like structures, which are
highly-ordered filamentous aggregates with increased resistance to quality-control mechanisms. Amyloid
structures are particularly threatening because they can self-propagate by recruiting proteins to their
filamentous termini, thus they can enable runaway protein aggregation. The naturally-occurring prions
(infectious proteins) of the yeast Saccharomyces cerevisiae are prime examples of this type of aggregation.
They polymerize into self-propagating amyloid fibers and can spread within yeast populations, thus altering
cellular phenotypes epigenetically via protein inactivation. However, unlike mammalian prion proteins that
underlie the fatal Transmissible Spongiform Encephalopathies (TSEs), yeast prions are generally tolerated by
their hosts, though their precise functions or detriments have been a subject of controversy. We propose using
yeast prions as inexpensive and safe models for pathological amyloid formation and propagation. How yeast
prion proteins interact with each other and with cellular quality-control machinery will have parallels to
pathological aggregation that occurs in neurodegenerative processes.
Objectives of our research plan include: 1 – Purify infectious prion amyloid directly from yeast cells and apply
biophysical methods to create a structural model of the infectious particles; 2 – Determine how eukaryotic
cellular quality-control mechanisms can distinguish and recognize prions and other types of macromolecular
protein aggregates for site-specific sequestration; 3 – Determine if naturally-occurring yeast prions have novel
functions

## Key facts

- **NIH application ID:** 9962449
- **Project number:** 5R35GM119790-05
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Yuanyi Feng
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,257
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962449

## Citation

> US National Institutes of Health, RePORTER application 9962449, Using naturally-occurring fungal prions as models of neurodegenerative protein misfolding (5R35GM119790-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962449. Licensed CC0.

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