# Mechanisms of Prion Aggregation and Species Barriers

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $339,063

## Abstract

PROJECT SUMMARY
Prions cause rapidly progressive neurodegenerative diseases clinically characterized by
cognitive impairment, cerebellar ataxia, and death within approximately seven months in the
case of sporadic Creutzfeldt-Jakob disease. Prion disorders occur following the auto-catalytic
conversion and aggregation of the cellular prion protein. The structural determinants of the prion
protein (PrP) that govern prion conversion and enable pathogenic prions to spread into and
through the CNS, targeting distinct cell populations, are unknown. A major goal of this proposal
is to understand the mechanisms that underlie prion conversion and cell-specific targeting. In
this project, we have previously pursued a broad range of approaches, from in vitro conversion
assays to newly generated transgenic mice, to determine the role of a PrP segment having
exceptionally high sequence variability among mammals, the β2-α2 loop (residues 165-175).
We discovered that the β2-α2 loop is a key segment of cellular PrP that impacts cross-species
prion transmission, impedes transmission of deer and elk prions to humans, and alters the
pathogenic prion conformation in a sequence-dependent manner. We also found that amino
acid substitutions in the loop led to de novo prion disease in mice. Finally, we determined that
elements of the PrP primary sequence, and not secondary structure, control prion conversion. In
this renewal, we aim to identify the key contributors to prion aggregate assembly. We build on
our observation that structural features of PrP together with host glycosaminoglycans drive
efficient prion conversion. First, we will identify the highly amyloidogenic interacting segments
that trigger prion conversion and will test rationally-designed inhibitors to block aggregation.
Second, we will define how post-translational modifications (PTM) of PrP modify the prion
plaque morphology and pathogenesis using mouse models expressing PTM variants of PrP that
were newly generated using CRISPR-Cas systems. Third, we will identify the sulfated
glycosaminoglycans bound to prion aggregates by liquid chromatography-mass spectrometry,
and will determine the impact of length, abundance, and pattern of heparan sulfate chains on
prion cell tropism and disease progression in mouse models. We expect that these studies will
define the PrP determinants and endogenous host factors that trigger prion conversion,
revealing new therapeutic targets to block prion assembly and spread.

## Key facts

- **NIH application ID:** 9948762
- **Project number:** 5R01NS069566-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,063
- **Award type:** 5
- **Project period:** 2011-03-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948762

## Citation

> US National Institutes of Health, RePORTER application 9948762, Mechanisms of Prion Aggregation and Species Barriers (5R01NS069566-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948762. Licensed CC0.

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