# Role of prion protein sialylation in prion diseases

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $706,228

## Abstract

Prions or PrPSc are proteinaceous infectious agents that consist of misfolded, self-replicating states of a
sialoglycoprotein called the prion protein or PrPC. Prions cause prion diseases, a family of transmissible
neurodegenerative maladies that have no treatment and are 100% lethal. A number of other amyloidogenic
proteins associated with several neurodegenerative diseases show prion-like self-replicating behavior in vitro
and in vivo. Nevertheless, PrPSc is unique in several important aspects. PrPSc shows incredibly high infectivity
titers, transmits efficiently between organisms via natural routes, and replicates in secondary lymphoid organs
(SLOs) in addition to the CNS. Moreover, prion diseases in humans can originate from transmission of animal
prion diseases. Why is PrPSc so incredibly transmissible and how does it escape the host immune system? In
the past, the amino acid sequences of host PrPC and strain-specific structures of donor PrPSc were identified as
key parameters that control prion replication. The current application is based on new evidence we have obtained
strongly suggesting prion transmission is linked to the extent of sialylation modification of PrPSc. The fact that N-
linked glycans of PrPC and PrPSc are sialylated was described more than 30 years ago. Yet, prion sialylation has
been completely ignored, mostly due our limited knowledge of the roles of sialylation in biology. In mammals,
sialylation of glycans is proposed to act as a part of a “self-associated molecular pattern”, helping the immune
system to discriminate between “self” and “altered self” or “non-self”. Here, we propose a new hypothesis that
sialylation of PrPSc controls both its fate and the outcomes of prion infection in an organism. In support of this
hypothesis, we found showed that administration of PrPSc with reduced sialylation levels to animals does not
cause prion disease or prion infection. The first aim of this application will provide a thorough evaluation of the
hypothesis that sialylation of PrPSc controls its fate in an organism, including its trafficking, clearance and, most
importantly, disease outcome. The second aim will elucidate the underlying mechanisms why secondary
lymphoid organs are highly permissive to prion transmission and, specifically, the role that sialylation plays in
cross-species prion transmission. The third aim will test a novel hypothesis that sialylation of PrPC creates a
replication barrier and, as such, controls the susceptibility of cells and/or tissues to prion infection. As a whole,
this work will establish the role of sialylation in prion diseases. This study will likely lead to new insight into our
understanding of prion propagation and transmission, which may provide new targets for therapeutic
intervention.

## Key facts

- **NIH application ID:** 9961482
- **Project number:** 5R01AI128925-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Ilia V Baskakov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $706,228
- **Award type:** 5
- **Project period:** 2017-07-06 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961482

## Citation

> US National Institutes of Health, RePORTER application 9961482, Role of prion protein sialylation in prion diseases (5R01AI128925-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9961482. Licensed CC0.

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