# Molecular basis of prion protein-induced neurodegeneration

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $58,953

## Abstract

PROJECT SUMMARY
Prion diseases are rare, invariably fatal neurodegenerative disorders with pathologic features in
common with Alzheimer’s disease, including extracellular protein aggregates, synaptic loss, and
neuritic dystrophy. In prion and Alzheimer’s disease models, depletion of neuronal cellular prion
protein (PrPC) ameliorates synaptic impairment and clinical disease, strongly
implicating neuronal PrPC expression in the altered signal transduction cascades that
may underlie synaptotoxicity and endolysosomal dysfunction. We have engineered the first
knock-in mouse model with a point mutation in Prnp that develops a striking and
severe spongiform encephalopathy, neuritic dystrophy, and altered post-synaptic receptor
phosphorylation, in the absence of prion aggregates. Cultured cortical neurons from these
knock-in mice show an increased sensitivity to glutamate and dendritic varicosities,
suggestive of excitotoxicity. Thus, this PrP knock-in model provides a unique opportunity to
elucidate key PrPC interactions and altered signal transduction pathways at the synapse
and to determine the molecular mechanisms that link PrPC to synaptic loss and
endolysosomal dysregulation. Our long-term goal is to understand how PrPC triggers
aberrant neuronal signaling that may drive impaired proteostasis and synaptotoxicity in prion
disease. Using cultured primary neurons and mice, we will first determine how the mutant
PrPC interactions impact pre- and post-synaptic neuronal protein levels and glutamate
receptor function. We will then identify how mutant PrPC dysregulates endolysosomal
and proteostatic activity. Finally, we use highly sensitive and quantitative proteomics to
define the PrP interactome and phosphoproteome network alterations in the brain by tandem
mass tag mass spectrometry analysis. For all aims, we will directly test how the findings from
the mutant PrPC-expressing brain compare to prion-infected mouse and human brain. These
studies are the first to target the neuronal endolysosomal and synaptic pathways in a
knock-in mouse model expressing mutant PrPC, and outcomes are expected to provide key
insights into the role of PrPC in synapse maintenance and the signaling pathways inciting
synaptic loss, thus revealing new therapeutic targets for prion disease.

## Key facts

- **NIH application ID:** 10898476
- **Project number:** 3RF1NS121992-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $58,953
- **Award type:** 3
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898476

## Citation

> US National Institutes of Health, RePORTER application 10898476, Molecular basis of prion protein-induced neurodegeneration (3RF1NS121992-01S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10898476. Licensed CC0.

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