# Structural Determinants of Mammalian Prion Aggregation

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $12,700

## Abstract

Project Summary:
Prion diseases are neurodegenerative disorders that pose a threat to human and environmental health. These
illnesses have genetic and nongenetic causes, can be environmentally acquired, and have the ability to remain
infectious in the absence of a host organism for extended periods. Aggregation of misfolded prion protein
(PrPSc) correlates with disease, but the mechanism behind aggregation is not fully understood, gravely
hindering the development of therapeutics to prevent fibrillation and sickness. The β2α2 loop of mammalian
prion protein has previously been demonstrated to be a key region implicated in disease transmission. A
crystal structure from a nine-residue segment encoding the β2α2 loop of the bank vole prion has demonstrated
structural characteristics and stability characteristic of full-length prion fibers. Building on this structure,
structures of PrP aggregates that convey information on stability and infectivity will be pursued. To achieve this
goal, ordered aggregates of PrP segments that have been described to play a role in disease transmission in
various species with a range of prion disease susceptibility will be biochemically and structurally characterized.
Constructs incorporating disease modulating regions will be recombinantly expressed, purified, and fibrillized to
assess stability, proteinase K resistance, and fiber morphologies. These properties will be compared against
those observed in fibrils derived from diseased animals. A combination of crystallography and single particle
Cryo-EM will be used to determine the atomic arrangement of each misfolded PrP. These aims will be
achieved through the application of frontier methods in macromolecular crystallography including electron
micro-diffraction (MicroED). The resulting structures will provide a molecular explanation for a nearly three-
hundred-year-old mystery in prion biology and protein pathology and will help distinguish infectious from non-
infectious amyloids, revealing structural code for prion transmission barriers.
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## Key facts

- **NIH application ID:** 10239229
- **Project number:** 5F31AI143368-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Calina Glynn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $12,700
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-09-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239229

## Citation

> US National Institutes of Health, RePORTER application 10239229, Structural Determinants of Mammalian Prion Aggregation (5F31AI143368-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10239229. Licensed CC0.

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