# Mechanisms of Prion Protein Toxicity

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $786,131

## Abstract

The overall goal of this application is to understand the mechanisms by which prions cause damage to
synapses, and establish and maintain a self-propagating infection in the CNS. We also wish to develop
pharmacologic therapies for these disorders based on our knowledge of the molecular and cellular
mechanisms underlying the disease process. Although the molecular templating model for prion propagation,
in which PrPC is converted into infectious PrPSc, is now widely accepted, the mechanisms by which prions
actually cause neurodegeneration have remained mysterious. There is now considerable evidence that cell-
surface PrPC mediates many of the neurotoxic effects of PrPSc, likely by serving as a receptor that binds PrPSc
during the first step of the prion conversion process. However, how this initiates downstream toxic signals in
the cytoplasm, and how these signals alter synaptic structure or function were largely unknown.
 The work we have accomplished during the previous grant cycle has provided key insights into this issue
by defining a PrPC/NMDAR/p38 MAPK signaling pathway that mediates the earliest effects of PrPSc
synaptotoxicity. Based on a combination of structural analysis and functional assays, we have proposed a
model in which the N-terminal domain of PrPC serves as a toxic effector that is regulated by specific docking
interactions with the C-terminal domain. Artificial disruption of this intramolecular interaction results in a variety
of toxic activities in cellular and transgenic models.
 In this renewal application, we propose, first, to elucidate how prion synaptotoxic signaling is initiated at
the cell surface. Second, we plan to dissect the intracellular signaling cascades that are activated by prions,
and how they result in synaptic dysfunction. Third, we will investigate the mechanisms by which cells establish
and maintain prion infection. We anticipate that the studies proposed here will provide powerful insights into
biological mechanisms that are common to multiple neurodegenerative disorders caused by toxic protein
aggregates in the brain, and will lead to the discovery of shared therapeutic approaches that can be used to
treat them.

## Key facts

- **NIH application ID:** 10298636
- **Project number:** 2R01NS065244-11A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** DAVID A HARRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $786,131
- **Award type:** 2
- **Project period:** 2010-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298636

## Citation

> US National Institutes of Health, RePORTER application 10298636, Mechanisms of Prion Protein Toxicity (2R01NS065244-11A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10298636. Licensed CC0.

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