# Molecular basis of prion protein-induced neurodegeneration

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,634,037

## Abstract

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:** 10199633
- **Project number:** 1RF1NS121992-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,634,037
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199633

## Citation

> US National Institutes of Health, RePORTER application 10199633, Molecular basis of prion protein-induced neurodegeneration (1RF1NS121992-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199633. Licensed CC0.

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