Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

Abstract

The interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson's disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer's disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

Structural details of amyloid β oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy

“…This article contains supporting information ( 13 , 19 , 24 , 25 , 26 , 27 , 32 , 33 , 34 , 40 , 41 , 47 , 48 , 53 , 54 , 55 , 75 , 76 , 77 , 78 , 95 , 96 , 97 , 98 , 99 ).…”

“…Several in vitro studies on the Aβ-PrP interaction suggest that Aβ oligos bind at two Lys-rich parts (residues 23–27 and ≈95–110) on PrP ( 35 , 36 , 37 , 38 , 39 , 40 ), but an additional involvement of the C terminus of PrP has also been suggested ( 21 ). Interestingly, the N terminus of human PrP is also able to bind oligomeric α-synuclein with high affinity ( 41 , 42 , 43 ). A structural study of insoluble PrP C -Aβ oligo complexes described them as a “hydrogel,” in which the Aβ(1−42) oligos were rigid, while PrP still has high molecular mobility ( 44 ).…”

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

“…8A). Though not assessed here, it appears likely that sPrP may act similarly against other proteinopathies, given the central role of PrP C as neuronal toxicity receptor [11, 14, 18]. It would also be interesting to assess whether sPrP bound to such oligomers and deposits may serve as an “eat-me” signal for internalization by phagocytic cells [115].…”

“…More recently, GPI-anchored PrP C has emerged as an important cell surface receptor for neurotoxic oligomers of β-sheet-rich peptides/proteins [6, 10–14] such as PrP Sc itself, Aβ, tau and α-synuclein, which are all mediators of neuronal dysfunction found in neurodegenerative diseases such as prion diseases, AD, tauopathies, and PD, respectively [14, 15]. The plasma membrane is the primary site for the detrimental interactions of such extracellular toxic conformers with the disordered N-terminal part of signaling-competent PrP C [16–18]. This binding causes synapto- and neurotoxic signaling (enabled by certain transmembrane proteins associating with PrP C [19, 20]) and, in the case of PrP Sc seeds, subsequent templated misfolding of native PrP C .…”

Recent advances in understanding and treatment of Parkinson’s disease

“…This α-synuclein pathology spreads and propagates in a prion-like fashion. Indeed, prion-like spread has been postulated as a mechanism of progression in many neurodegenerative diseases besides PD (synucleinopathies and other proteinopathies) 10 – 12 .…”