# Determining pathogenic PrPC-induced signaling pathways in human iPSC-induced neurons

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $434,500

## Abstract

Prion diseases are rare, invariably fatal neurodegenerative disorders characterized by rapid
cognitive and motor decline. Certain pathologic features overlap with Alzheimer’s disease,
including protein aggregates and massive synapse loss in the brain, yet the sequence of events
driving synaptic loss is incompletely understood. In prion and Alzheimer’s disease models,
neuronal cellular prion protein (PrPC) reportedly binds oligomers and elicits a cascade of
intracellular signals, whereas PrPC deletion ameliorates synaptic impairment, strongly implicating
neuronal PrPC in altering signal transduction events. Using unbiased transcriptomics on prion-
infected mouse brain, we have found that immediate early genes are among the earliest, most
significantly upregulated genes in the hippocampus, suggestive of heightened neuronal activity.
We have also discovered early aberrant neuronal kinase activity in the hippocampus and cortex.
Notably, similar kinase modifications were incited in human iPSC-induced neurons within 2 hours
of triggering PrPC. In Aim 1, we will determine how an anti-PrP antibody ligand or purified
infectious prion oligomers induce synaptic kinase signaling in human iPSC-induced neurons. In
Aim 2, we use highly sensitive and quantitative proteomics to identify the PrPC- transmembrane
signaling network components and network alterations in human neurons triggered by a prion
protein ligand. These studies are the first to pursue PrPC-initiated signaling pathways in human
neurons, and are expected to establish the signaling parameters and downstream consequences
as well as provide insight into events leading to synapse loss in disease.

## Key facts

- **NIH application ID:** 10791127
- **Project number:** 1R21NS135426-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791127

## Citation

> US National Institutes of Health, RePORTER application 10791127, Determining pathogenic PrPC-induced signaling pathways in human iPSC-induced neurons (1R21NS135426-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10791127. Licensed CC0.

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