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.
Highlights
The interaction of prion protein (PrP) and α-synuclein oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies
Aβ oligomers (AβO) binds to the human PrP (huPrP) N-terminus[15,16,17,18,19], which triggers a neurotoxic signaling cascade that may be responsible for early synaptic dysfunction in Alzheimer’s disease (AD), involving metabotropic glutamate receptor 5, Fyn kinase, and N-methyl-Daspartate (NMDA) receptors[20,21]
High-molecular-weight complexes of αSyn oligomers (αSynO) and huPrP. αSynO was reported to bind to membrane-anchored PrPC and activate Fyn kinase via metabotropic glutamate receptor 5, leading to phosphorylation of N-methyl-D-aspartate receptors (NMDAR) and to elevated intracellular calcium levels (Fig. 1a)[9]
Summary
The interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Substantial evidence suggests that it is the smaller and more diffusible oligomeric assemblies that are triggering early pathogenesis[3,4,5,6,7] Both αSyn oligomers (αSynO) and Aβ oligomers (AβO) can induce synaptic dysfunction and inhibit hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory[5,8,9]. Apart from their role in PD, αSyn aggregates are the pathological hallmarks of dementia with Lewy bodies (DLB), multiple system atrophy, and other neurodegenerative diseases, collectively termed synucleinopathies[10]. On the other hand, questioned direct binding of αSynO to huPrP24
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