Role of cellular prion protein in interneuronal amyloid transmission

Abstract

Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrP) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrP interaction takes place in two differently charged clusters of PrP. In addition to β-amyloid, participation of PrP in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrP as a putative receptor for amyloid proteins and the physiological consequences of these interactions.

The Quest for Cellular Prion Protein Functions in the Aged and Neurodegenerating Brain

“…Since Prnp expression is not mandatory for α-synuclein transport in the mouse brain [258], it is tempting to consider that role in the update and transport to be a collateral effect on the principal neuroprotective role of PrP C in the disease. In this respect, we also must recall that both our group and Aulic et al [157] indicated that PrP C is a receptor for the fibrillar forms of α-synuclein [21,257,259]. However, as it has been reported that PrP C does not bind to oligomeric species of α-synuclein [67] in contrast to [23], additional studies are needed to ascertain whether oligomeric α-synuclein also mediates similar effects to ADDLs though PrP C interaction.…”

“…In addition, Younan and colleagues have shown that PrP C inhibits fiber formation by trapping free ADDLs and causing disassembly of preformed Aβ fibrils [213]. The authors point to two charged clusters in the N-terminal domain of PrP C as being responsible for Aβ-PrP C binding: (aa [95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] and (aa [23][24][25][26][27] [21,155,213]. At this point, it is important to keep in mind that the activity of PrP C is finely regulated by its dimerization and that PrP C homodimers stimulate the production of PrPN1, which in turn can bind to Aβ with high affinity, blocking transformation into soluble and toxic ADDLs [136,160,161,164].…”

“…In recent years, the scientific community has focused attention on defining the term "prion-like" or "prionoid" to describe other proteins with behavior similar to prions in terms of self-aggregation and spreading properties [10][11][12][13][14]. Proteins implicated in different NDDs, including Huntingtin [15], α-synuclein [16][17][18][19][20][21][22][23], amyloid-β (Aβ) [24][25][26], and tau [27][28][29][30][31], are currently seen in numerous studies as prion-like proteins. In fact, most of them display amino acid domains in their sequence that determine their specific self-aggregation properties [32,33].…”

Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease

“…Although additional receptors may contribute to mediation of AβO action, recent investigations indicate that PrP C supposedly plays a primary role (reviewed by Del Rio [ 122 ]). PrP C is a glycosylphosphatidylinositol (GPI)-anchored protein.…”

“…Interestingly, it was shown that PrP c also appears to be relevant in α-synucleopathies, such as PD, participating in α-synuclein binding and brain spreading [ 122 ].…”