On the role of the cellular prion protein in the uptake and signaling of pathological aggregates in neurodegenerative diseases

Neurodegenerative disorders are associated with intra- or extra-cellular deposition of aggregates of misfolded insoluble proteins. These deposits composed of tau, amyloid-\u3b2 or \u3b1-synuclein spread from cell to cell, in a prion-like manner. Novel evidence suggests that the circulating soluble oligomeric species of these misfolded proteins could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Recent convincing data support the proposition that the cellular prion protein, PrPC, act as a toxicity-inducing receptor for amyloid-\u3b2 oligomers. As a consequence, several studies focused their investigations to the role played by PrPC in binding other protein aggregates, such as tau and \u3b1-synuclein, for its possible common role in mediating toxic signalling. The biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, could lead to relevant therapeutic implications. Here we describe the structure of PrPC and the proposed interplay with its pathological counterpart PrPSc and then we recapitulate the most recent findings regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins

N-Glycans and Glycosylphosphatidylinositol-Anchor Act on Polarized Sorting of Mouse PrPC in Madin-Darby Canine Kidney Cells

The cellular prion protein (PrPC) plays a fundamental role in prion disease. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein with two variably occupied N-glycosylation sites. In general, GPI-anchor and N-glycosylation direct proteins to apical membranes in polarized cells whereas the majority of mouse PrPC is found in basolateral membranes in polarized Madin-Darby canine kidney (MDCK) cells. In this study we have mutated the first, the second, and both N-glycosylation sites of PrPC and also replaced the GPI-anchor of PrPC by the Thy-1 GPI-anchor in order to investigate the role of these signals in sorting of PrPC in MDCK cells. Cell surface biotinylation experiments and confocal microscopy showed that lack of one N-linked oligosaccharide leads to loss of polarized sorting of PrPC. Exchange of the PrPC GPI-anchor for the one of Thy-1 redirects PrPC to the apical membrane. In conclusion, both N-glycosylation and GPI-anchor act on polarized sorting of PrPC, with the GPI-anchor being dominant over N-glycans