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.
Prion diseases are a group of fatal, transmissible, age-dependent neurodegenerative diseases that are caused by aggregation and misfolding of sialoglycoprotein called the prion protein. While sialylation is known to play a key role in recognition of pathogens by the host immune system, little is known about the role of sialylation in interactions of prions with a host. The current project seeks to fill this gap and establish the role of sialylation in prion diseases.
| Srivastava, Saurabh; Katorcha, Elizaveta; Makarava, Natallia et al. (2018) Inflammatory response of microglia to prions is controlled by sialylation of PrPSc. Sci Rep 8:11326 |
| Makarava, Natallia; Savtchenko, Regina; Lasch, Peter et al. (2018) Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein. Acta Neuropathol Commun 6:92 |
