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 fibrils, which was also confirmed 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.
Highlights
Α-Syn amyloid fibrils are able to interfere with prion replication through the binding to PrPC
The resulting mouse α-Syn fibrils were subjected to biochemical analysis (Supplementary Fig. S1e) and the amyloids were structurally characterized by atomic force microscopy (AFM) (Supplementary Fig. S2)[21]
Several independent studies described the accumulation of α-Syn pathology after intracerebral inoculation of recombinant α-Syn fibrils in wild type[9, 10], and in transgenic mice[7, 35, 36]
Summary
Suzana Aulić[1], Lara Masperone[1], Joanna Narkiewicz[1], Elisa Isopi[2], Edoardo Bistaffa[1,3], Elena Ambrosetti[4,5], Beatrice Pastore[1], Elena De Cecco[1], Denis Scaini[4,6], Paola Zago[1], Fabio Moda[3], Fabrizio Tagliavini3 & Giuseppe Legname 1,4. The in vitro data revealed that the presence of PrPC fosters the higher uptake of α-Syn amyloid fibrils, which was confirmed in vivo in wild type (Prnp+/+) compared to PrP knock-out (Prnp−/−) mice. Since confocal microscopy experiments revealed the co-localization between PrPC attached to the cell membrane and exogenously added α-Syn amyloids (Fig. 1c) we moved on to better characterize the molecular interaction between the two proteins In this context, enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) experiments were performed. Injection of α-Syn amyloid fibrils in mice induced the formation of LB-like aggregates in different brain areas (Fig. 2a). In agreement with in vitro results, the data show that in general Prnp−/− mice accumulate less PK-resistant α-Syn aggregates in all areas analyzed (Fig. 2c,d). Amyloid seeding assay (ASA)[34] confirmed the data observed in ScN2a cells, and in PMCA experiments (Supplementary Fig. S17)
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