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?-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication.

ABSTRACT: The precise molecular mechanism of how misfolded ?-synuclein (?-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP^C) in mediating the uptake and the spread of recombinant ?-Syn amyloids. The in vitro data revealed that the presence of PrP^C fosters the higher uptake of ?-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp ^+/+) compared to PrP knock-out (Prnp ^-/-) mice. Additionally, the presence of ?-Syn amyloids blocked the replication of scrapie prions (PrP^Sc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrP^C is mediating the internalization of ?-Syn amyloids, PrP^Sc is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of ?-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.

SUBMITTER: Aulic S

PROVIDER: S-EPMC5577263 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication.

Aulić Suzana S Masperone Lara L Narkiewicz Joanna J Isopi Elisa E Bistaffa Edoardo E Ambrosetti Elena E Pastore Beatrice B De Cecco Elena E Scaini Denis D Zago Paola P Moda Fabio F Tagliavini Fabrizio F Legname Giuseppe G

Scientific reports 20170830 1

The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrPC) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the presence of PrPC fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp +/+) compared to PrP knock-out (Prnp -/-</s ...[more]

PMID: 28855681

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Project description:Cellular entry of nonenveloped and enveloped viruses is often accompanied by dramatic conformational changes within viral structural proteins. These rearrangements are triggered by a variety of mechanisms, such as low pH, virus-receptor interactions, and virus-host chaperone interactions. Reoviruses, a model system for entry of nonenveloped viruses, undergo a series of disassembly steps within the host endosome. One of these steps, infectious subviral particle (ISVP)-to-ISVP* conversion, is necessary for delivering the genome-containing viral core into host cells, but the physiological trigger that mediates ISVP-to-ISVP* conversion during cell entry is unknown. Structural studies of the reovirus membrane penetration protein, ?1, predict that interactions between ?1 and negatively charged lipid head groups may promote ISVP* formation; however, experimental evidence for this idea is lacking. Here, we show that the presence of polyanions (SO4(2-) and HPO4(2-)) or lipids in the form of liposomes facilitates ISVP-to-ISVP* conversion. The requirement for charged lipids appears to be selective, since phosphatidylcholine and phosphatidylethanolamine promoted ISVP* formation, whereas other lipids, such as sphingomyelin and sulfatide, either did not affect ISVP* formation or prevented ISVP* formation. Thus, our work provides evidence that interactions with membranes can function as a trigger for a nonenveloped virus to gain entry into host cells.Cell entry, a critical stage in the virus life cycle, concludes with the delivery of the viral genetic material across host membranes. Regulated structural transitions within nonenveloped and enveloped viruses are necessary for accomplishing this step; these conformational changes are predominantly triggered by low pH and/or interactions with host proteins. In this work, we describe a previously unknown trigger, interactions with lipid membranes, which can induce the structural rearrangements required for cell entry. This mechanism operates during entry of mammalian orthoreoviruses. We show that interactions between reovirus entry intermediates and lipid membranes devoid of host proteins promote conformational changes within the viral outer capsid that lead to membrane penetration. Thus, this work illustrates a novel strategy that nonenveloped viruses can use to gain access into cells and how viruses usurp disparate host factors to initiate infection.

Dataset Information

?-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication.

Publications

α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication.

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