Neuroprotective and Neurotoxic Signaling by the Prion Protein

Abstract

Prion diseases in humans and animals are characterized by progressive neurodegeneration and the formation of infectious particles called prions. Both features are intimately linked to a conformational transition of the cellular prion protein (PrP(C)) into aberrantly folded conformers with neurotoxic and self-replicating activities. Interestingly, there is increasing evidence that the infectious and neurotoxic properties of PrP conformers are not necessarily coupled. Transgenic mouse models revealed that some PrP mutants interfere with neuronal function in the absence of infectious prions. Vice versa, propagation of prions can occur without causing neurotoxicity. Consequently, it appears plausible that two partially independent pathways exist, one pathway leading to the propagation of infectious prions and another one that mediates neurotoxic signaling. In this review we will summarize current knowledge of neurotoxic PrP conformers and discuss the role of PrP(C) as a mediator of both stress-protective and neurotoxic signaling cascades.

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

“…PrP␣3M Mutants Accumulate as CtmPrP-The above biochemical features were reminiscent of previously described de novo formation of either PrP Sc -like or CtmPrP forms (6,40,41,48). To assess the conformation adopted by PrP␣3M mutants, we analyzed the detergent solubility and the resistance to proteases of HaPrPDS (1, 6).…”

“…Also, the size similarity of WT HaPrP and HaPrPDS bands upon combined PNGase F and PIPLC digestion indicates that in both PrP chains the N-terminal signal sequence has been removed. Taken together, the post-translational processing of HaPrPDS, representative here of PrP3␣M mutants, indicates removal of the N-terminal signal sequence, immature glycosylation, and the presence of a GPI anchor.PrP␣3M Mutants Accumulate as CtmPrP-The above biochemical features were reminiscent of previously described de novo formation of either PrP Sc -like or CtmPrP forms (6,40,41,48). To assess the conformation adopted by PrP␣3M mutants, we analyzed the detergent solubility and the resistance to proteases of HaPrPDS (1, 6).…”

Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders

“…In the AD field, for example, this hypothesis solves one of the most disputed issues, that regarding the 'pathogenic' vs. 'protective roles of Aβ and its various IICs, which has been highlighted in dozens if not hundreds of publications (e.g., see 56,68,69,[90][91][92][93]; same is true for other proteins in this group (e.g., see 24,94,95). According to this new, unifying hypothesis, which integrates both perspectives, the Aβ and its IICs can have both 'protective' or 'pathogenic' attributes, whether their activity is defined at the cellular/tissue level or at the organism level.…”

Mechanisms of Cell Death in the Transmissible Spongiform Encephalopathies

“…A key recent finding in PrP C knockout mice was defects in the maintenance of the myelin sheath surrounding peripheral nerves, a phenotype that appeared specifically to result from depletion of PrP C from neurons (Bremer et al, 2010). Thus, prion protein knockout mice have a range of physiological phenotypes primarily related to neuronal functions and this has led to a consensus that PrP C is a neuroprotective molecule, although it is not clear how, specifically, this neuroprotection is manifest (Resenberger et al, 2011b). A thorough review of prion protein function is beyond the scope of this chapter but, in the context of TSE disease, a key question is whether the loss of a neuroprotective function of PrP C plays a role in neurodegenerative mechanisms.…”