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 fbrils, which was also confrmed in vivo in wild type (Prnp+/+) compared to PrP knock-out (Prnp−/−) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrPSc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrPC is mediating the internalization of α-Syn amyloids, PrPSc is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.
Titolo: | α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication |
Autori: | |
Data di pubblicazione: | 2017 |
Stato di pubblicazione: | Pubblicato |
Rivista: | |
Abstract: | 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 fbrils, which was also confrmed in vivo in wild type (Prnp+/+) compared to PrP knock-out (Prnp−/−) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrPSc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrPC is mediating the internalization of α-Syn amyloids, PrPSc is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course. |
Handle: | http://hdl.handle.net/11368/2931308 |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/s41598-017-10236-x |
URL: | https://www.nature.com/articles/s41598-017-10236-x#Sec22 |
Appare nelle tipologie: | 1.1 Articolo in Rivista |
File in questo prodotto:
File | Descrizione | Tipologia | Licenza | |
---|---|---|---|---|
s41598-017-10236-x.pdf | Documento in Versione Editoriale | ![]() | Open Access Visualizza/Apri | |
41598_2017_10236_MOESM1_ESM.pdf | supplementary material | Altro materiale allegato | ![]() | Open Access Visualizza/Apri |