# Replication mechanism of human prions

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $516,757

## Abstract

ABSTRACT
Prions are unique, protein-only infectious agents that are responsible for a group of fatal neurodegenerative
diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle and
chronic wasting disease in deer and elk. Human prion diseases are especially poorly understood, largely due
to their vast phenotypic heterogeneity that arises from a large spectrum of diverse human prion strains. It is
generally accepted that the prion agent multiplies by binding to normal prion protein (PrPC) and converting it
into a conformationally distinct pathogenic molecule (PrPSc), but the mechanism of this process remains
unclear. A growing number of studies suggest a critical role in prion disease pathogenesis of small, relatively
protease sensitive oligomers that appear to control two fundamental steps in the disease pathogenesis: prion
replication rate and toxicity. One of the primary objectives of the proposed research is to advance molecular
level understanding of the properties of oligomeric PrPSc (oPrPSc) and the mechanism by which these
oligomers contribute to the pathogenic process in different phenotypes of sporadic Creutzfeldt-Jakob disease
(sCJD). The first Specific Aim is to characterize the structural organization of oPrPSc and define the role of this
organization in the replication, propagation and toxicity of the most common strains of sCJD. The second Aim
is to identify early critical conformational steps in the interaction between PrPC and oPrPSc, the steps that likely
play a major role in triggering toxic signaling, creating human prions and controlling prion evolution. If
successful, the proposed studies should not only shed new light on the pathogenic mechanism in human prion
disorders, but also provide a basis for understanding the relationship between PrPSc structure and strain
properties of human prions.

## Key facts

- **NIH application ID:** 9853854
- **Project number:** 5R01NS103848-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** WITOLD K SUREWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $516,757
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853854

## Citation

> US National Institutes of Health, RePORTER application 9853854, Replication mechanism of human prions (5R01NS103848-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853854. Licensed CC0.

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