The cellular prion protein (PrPC) as neuronal receptor for α-synuclein

Abstract

The term 'prion-like' is used to define some misfolded protein species that propagate intercellularly, triggering protein aggregation in recipient cells. For cell binding, both direct plasma membrane interaction and membrane receptors have been described for particular amyloids. In this respect, emerging evidence demonstrates that several β-sheet enriched proteins can bind to the cellular prion protein (PrP^C). Among other interactions, the physiological relevance of the binding between β-amyloid and PrP^C has been a relevant focus of numerous studies. At the molecular level, published data point to the second charged cluster domain of the PrP^C molecule as the relevant binding domain of the β-amyloid/PrP^C interaction. In addition to β-amyloid, participation of PrP^C in binding α-synuclein, responsible for neurodegenerative synucleopathies, has been reported. Although results indicate relevant participation of PrP^C in the spreading of α-synuclein in living mice, the physiological relevance of the interaction remains elusive. In this comment, we focus our attention on summarizing current knowledge of PrP^C as a receptor for amyloid proteins and its physiological significance, with particular focus on α-synuclein.

Keywords: LAG3; Parkinson disease; PrPC; charged cluster domain; interneuronal transport; neurodegeneration; α-synuclein.

FIGURE 1.

Increased p-α-synuclein aggregate labeling in the motor neocortex in Tga20 mice compared with B6.129 (ZH1 Prnp^0/0) and ZH3 Prnp^0/0 mice. Examples of p-α-synuclein aggregates in the cortex of B6.129 (ZH1) Prnp^0/0 (a); ZH3 Prnp^0/0 (b) and Tga20 mice (c) injected with recombinant mouse α-synuclein fibrils in the post-commissural striatum. Note the relevant accumulation of p- α-synuclein in intracellular deposits of retrograde labeled neurons in cortical layer V of Tga20 mice. Scale bar: a = 100 µm pertains to b and c.