# Self-Propagating Mechanism of Prion Diseases

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $508,003

## Abstract

Prion diseases are transmissible neurodegenerative maladies that are caused by misfolding and
aggregation of the prion protein and display diverse disease phenotypes. Regardless of a disease
phenotype, chronic inflammation of the glia is considered to be central to disease pathogenesis. The
diversity of disease phenotypes is attributed to the ability of normal form of the prion protein or PrPC to
misfold into multiple, structurally distinct, self-replicating PrPSc states referred to as prion strains or
subtypes. The question of how different PrPSc structures elicit diverse pathological response by CNS
remains poorly understood. In fact, the relationship between strain-specific PrPSc structures and CNS
responses remains empirical, whereas a mechanism that would describe their relationship in a predictable
manner is lacking. Moreover, it remains unclear what molecular features of PrPSc are responsible for
chronic inflammation and neurodegeneration. Lack of this knowledge represents a key gap in the field. The
current application proposes a novel mechanism, according to which carbohydrate epitopes formed by N-
linked glycans on PrPSc surface determine strain-specific response of CNS. The key element of this new
mechanism is a selective recruitment of PrPC glycoforms by PrPSc, which is governed by strain-specific
PrPSc structures and results in strain-specific patterns of carbohydrate epitopes on PrPSc surface. As a part
of this mechanism, we propose that deposition of PrPSc triggers phenotypic changes in glia, where the
resulting glial phenotypes are determined by the patterns of carbohydrate epitopes on PrPSc surface. For
rigorous testing of above mechanism, we developed biochemical approaches for manipulating PrPSc
carbohydrate patterns in vitro, and generated new PrPSc states with unique glycosylation status in animals.
Aim 1 will test whether PrPC glycoforms are recruited into PrPSc selectively and in a strain-specific manner.
Aim 2 will examine a relationship between PrPSc carbohydrate epitopes and activation states of glia,
whereas Aim 3 will elucidate molecular features of PrPSc responsible for inflammation and
neurodegeneration. Multidisciplinary approaches, including animal pathology, primary cell cultures, mass
spectrometry and biochemical techniques, will be employed to elucidate the mechanisms behind chronic
inflammation and neurodegeneration. This study will provide a rigorous test of the new hypothesis on the
role of PrPSc carbohydrate epitopes in determining functional states of glia. When the project is completed,
a comprehensive picture of the role of N-linked glycans in prion diseases will emerge. It is anticipated that
this study will lead to new targets for therapeutic intervention against prion diseases.

## Key facts

- **NIH application ID:** 10109149
- **Project number:** 5R01NS045585-19
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Ilia V Baskakov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,003
- **Award type:** 5
- **Project period:** 2003-09-30 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109149

## Citation

> US National Institutes of Health, RePORTER application 10109149, Self-Propagating Mechanism of Prion Diseases (5R01NS045585-19). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10109149. Licensed CC0.

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