α-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 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.

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…During shedding, PrP C is released from the plasma membrane by a disintegrin and metalloproteinase (ADAM) enzyme, namely, ADAM10, in a glycosylated form without the GPI anchor and designated as “shed PrP.” Although definite functions of “shed PrP” are not known to date, the shedding process regulates the membrane levels of PrP C and thus its functions at the cell surface. Similar to α‐synuclein, recent work by Jarosz‐Griffiths et al found that the toxicity and cellular binding of Aβ oligomers can be reduced by shedding of PrP C , thereby pointing towards a contribution as a receptor in AD. Moreover, PrP C is expressed in immune cells as well, particularly on mast cells .…”

Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

“…Recently, different studies reported the existence of αSyn interactors that may be involved in the cell‐to‐cell transmission of αSyn pathology (Fig. ).…”

“…More recently, PrP C was identified as a possible sensor for αSyn aggregates . In addition to interacting with αSyn and amyloid‐β (Aβ), it was recently proposed that PrP C might act as a conformation‐specific sensor for disease‐associated proteins, suggesting a more general role in the pathogenesis of various neurodegenerative diseases .…”

“…αSyn species injected in the substantia nigra pars compacta were found in the cortex, striatum, thalamus, and hippocampus 5 months after injection. In contrast, the accumulation and spreading of αSyn were reduced in PrP C ‐knockout (KO) mice …”

“…Recent studies indicate that misfolded α‐synuclein (αSyn) species can be propagated intercellularly, triggering protein aggregation in recipient cells. Interestingly, the direct interaction of αSyn with the cellular prion protein (PrP C ) was shown to be important for the transfer of αSyn between cells . Recently, we found that the interaction of αSyn oligomers with PrP C induces the phosphorylation of Fyn kinase via metabotropic glutamate receptor 5 (mGluR5), and the consequent phosphorylation of the N‐methyl‐ d ‐aspartate receptor 2B subunit (NMDAR2B).…”