# Mechanisms of Prion Spread and Neuronal Toxicity

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $698,643

## Abstract

Synaptic dysfunction and neuritic dystrophy are prominent pathologic features of the prion- and 
Alzheimer’s disease-affected brain. Ubiquitinated protein inclusions are also commonly observed, 
providing strong evidence of impaired proteostatic pathways. Ubiquitination of cell membrane 
proteins and clearance through the ESCRT pathway (endosomal sorting complex required for 
transport) is critical to maintaining synaptic homeostasis. Here we will deeply investigate the 
ESCRT pathway contributions to disrupted synaptic homeostasis in prion disease. In prion-infected mice, we have found markedly reduced ESCRT-0 (an Hrs and STAM1 protein complex) 
and an enrichment of ubiquitinated proteins in synaptosomes. Strikingly, depleting neuronal Hrs 
in prion-infected mice shortened survival time and accelerated the degeneration of synapses, 
biochemically and structurally. Additionally, in a longitudinal study of the prion-infected 
hippocampus, we found an upregulation in the synaptic activity response gene, Arc/Arg3.1, and 
a chronic elevation in phosphorylated CaMKII and phosphorylated AMPA receptors, suggestive 
of enhanced and altered synapse function beginning in early disease. Our long-term goal is to 
decipher how prion and amyloid-β oligomers disrupt signaling pathways linked to the cellular prion 
protein, inducing proteostatic dysfunction and synaptic degeneration. Using electrophysiology, 
correlative light-electron microscopy, and proteomics on uninfected and prion-infected cultured 
neurons, we will first determine how Hrs expression impacts synapses, assessing activity, pre-and post-synaptic proteins, structure, and signaling. We will then test how distinct prion 
conformers impact the ESCRT pathway and neuronal signaling at glutamatergic synapses. 
Finally, we will investigate the contribution of glutamate receptor activity to prion spread and 
neurodegeneration. We will directly test how the findings in these genetically manipulated models 
compare to human prion-affected brain. These studies are the first to test how neuronal activity 
impacts prion dissemination, synaptic degeneration, and disease progression, and outcomes are 
expected to provide key insights into the deregulated synaptic signaling that drives neuron loss, 
thus revealing new therapeutic targets.

## Key facts

- **NIH application ID:** 10766823
- **Project number:** 5R37NS076896-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $698,643
- **Award type:** 5
- **Project period:** 2023-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766823

## Citation

> US National Institutes of Health, RePORTER application 10766823, Mechanisms of Prion Spread and Neuronal Toxicity (5R37NS076896-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10766823. Licensed CC0.

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