Separate mechanisms act concurrently to shed and release the prion protein from the cell

The cellular prion protein (PrP^C) is attached to the cell membrane via its glycosylphosphatidylinositol (GPI)-anchor and is constitutively shed into the extracellular space. Here, three different mechanisms are presented that concurrently shed PrP^C from the cell. The fast α-cleavage released a N-terminal fragment (N1) into the medium and the extreme C-terminal cleavage shed soluble full-length (FL-S) PrP and C-terminally cleaved (C1-S) fragments outside the cell. Also, a slow exosomal release of full-length (FL) and C1-fragment (C1) was demonstrated. The three separate mechanisms acting simultaneously, but with different kinetics, have to be taken into consideration when elucidating functional roles of PrP^C and also when processing of PrP^C is considered as a target for intervention in prion diseases. Further, in this study it was shown that metalloprotease inhibitors affected the extreme C-terminal cleavage and shedding of PrP^C. The metalloprotease inhibitors did not influence the α-cleavage or the exosomal release. Taken together, these results are important for understanding the different mechanisms acting in parallel in the shedding and cleavage of PrP^C.     

Separate mechanisms act concurrently to shed and release the prion protein from the cell

The cellular prion protein (PrP^C) is attached to the cell membrane via its glycosylphosphatidylinositol (GPI)-anchor and is constitutively shed into the extracellular space. Here, three different mechanisms are presented that concurrently shed PrP^C from the cell. The fast α-cleavage released a N-terminal fragment (N1) into the medium and the extreme C-terminal cleavage shed soluble full-length (FL-S) PrP and C-terminally cleaved (C1-S) fragments outside the cell. Also, a slow exosomal release of full-length (FL) and C1-fragment (C1) was demonstrated. The three separate mechanisms acting simultaneously, but with different kinetics, have to be taken into consideration when elucidating functional roles of PrP^C and also when processing of PrP^C is considered as a target for intervention in prion diseases. Further, in this study it was shown that metalloprotease inhibitors affected the extreme C-terminal cleavage and shedding of PrP^C. The metalloprotease inhibitors did not influence the α-cleavage or the exosomal release. Taken together, these results are important for understanding the different mechanisms acting in parallel in the shedding and cleavage of PrP^C.     

Proteomics applications in prion biology and structure

Prion diseases are a heterogeneous class of fatal neurodegenerative disorders associated with misfolding of host cellular prion protein (PrP^C) into a pathological isoform, termed PrP^Sc. Prion diseases affect various mammals, including humans, and effective treatments are not available. Prion diseases are distinguished from other protein misfolding disorders – such as Alzheimer’s or Parkinson’s disease – in that they are infectious. Prion diseases occur sporadically without any known exposure to infected material, and hereditary cases resulting from rare mutations in the prion protein have also been documented. The mechanistic underpinnings of prion and other neurodegenerative disorders remain poorly understood. Various proteomics techniques have been instrumental in early PrP^Sc detection, biomarker discovery, elucidation of PrP^Sc structure and mapping of biochemical pathways affected by pathogenesis. Moving forward, proteomics approaches will likely become more integrated into the clinical and research settings for the rapid diagnosis and characterization of prion pathogenesis.     

PrP overdrive

Knockout of the cellular prion protein (PrP^C) in mice is tolerated, as is complete elimination of the protein’s N-terminal domain. However, deletion of select short segments between the N- and C-terminal domains is lethal. How can one reconcile this apparent paradox? Research over the last few years demonstrates that PrP^C undergoes α-cleavage in the vicinity of residue 109 (mouse sequence) to release the bioactive N1 and C1 fragments. In biophysical studies, we recently characterized the action of relevant members of the ADAM (A Disintegrin And Metalloproteinase) enzyme family (ADAM8, 10, and 17) and found that they all produce α-cleavage, but at 3 distinct cleavage sites, with proteolytic efficiency modulated by the physiologic metals copper and zinc. Remarkably, the shortest lethal deletion segment in PrP^C fully encompasses the three α-cleavage sites. Analysis of all reported PrP^C deletion mutants suggests that elimination of α-cleavage, coupled with retention of the protein’s N-terminal residues, segments 23–31 and longer, confers the lethal phenotype. Interestingly, these N-terminal residues are implicated in the activation of several membrane proteins, including synaptic glutamate receptors. We propose that α-cleavage is a general mechanism essential for downregulating PrP^C’s intrinsic activity, and that blockage of proteolysis leads to constitutively active PrP^C and consequent dyshomeostasis.     

Naturally prion resistant mammals

Each known abnormal prion protein (PrP^Sc) is considered to have a specific range and therefore the ability to infect some species and not others. Consequently, some species have been assumed to be prion disease resistant as no successful natural or experimental challenge infections have been reported. This assumption suggested that, independent of the virulence of the PrP^Sc strain, normal prion protein (PrP^C) from these ‘resistant’ species could not be induced to misfold. Numerous in vitro and in vivo studies trying to corroborate the unique properties of PrP^Sc have been undertaken. The results presented in the article “Rabbits are not resistant to prion infection” demonstrated that normal rabbit PrP^C, which was considered to be resistant to prion disease, can be misfolded to PrP^Sc and subsequently used to infect and transmit a standard prion disease to leporids. Using the concept of species resistance to prion disease, we will discuss the mistake of attributing species specific prion disease resistance based purely on the absence of natural cases and incomplete in vivo challenges. The BSE epidemic was partially due to an underestimation of species barriers. To repeat this error would be unacceptable, especially if present knowledge and techniques can show a theoretical risk. Now that the myth of prion disease resistance has been refuted it is time to re-evaluate, using the new powerful tools available in modern prion laboratories, whether any other species could be at risk.     

The P’s and Q’s of cellular PrP-Aβ interactions

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP^C, is converted to a disease-associated, β-sheet enriched isoform called PrP^Sc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,¹ but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP^Sc in prion diseases.^2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,⁴ and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau^5,6 and α-synuclein in the case of Parkinson Disease.^7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”⁹, and lies outside the scope of this particular review where we will focus upon PrP^C. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP^C,¹⁰ (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP^C (Fig. 1) (3) similar lipid raft environments for PrP^C and APP processing machinery,^11-13 and perhaps in consequence, overlaps in repertoire of the PrP^C and APP protein interactors (“interactomes”),^14,15 and (4) rare kindreds with mixed AD and prion pathologies.¹⁶ Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.     

A closer look at prion strains

Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrP^Sc), a pathogenic isoform of the host-encoded cellular prion protein (PrP^C). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrP^Sc conformational and aggregation states.

Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrP^Sc biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages.

This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves.     

The PrPC C1 fragment derived from the ovine A136R154R171 PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrPC protein in vitro

Expression of the cellular prion protein (PrP^C) is crucial for the development of prion diseases. Resistance to prion diseases can result from reduced availability of the prion protein or from amino acid changes in the prion protein sequence. We propose here that increased production of a natural PrP α-cleavage fragment, C1, is also associated with resistance to disease. We show, in brain tissue, that ARR homozygous sheep, associated with resistance to disease, produced PrP^C comprised of 25% more C1 fragment than PrP^C from the disease-susceptible ARQ homozygous and highly susceptible VRQ homozygous animals. Only the C1 fragment derived from the ARR allele inhibits in-vitro fibrillisation of other allelic PrP^C variants. We propose that the increased α-cleavage of ovine ARR PrP^C contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the significant reduction in PrP^C β-cleavage product C2 in sheep of the ARR/ARR genotype compared to ARQ/ARQ and VRQ/VRQ genotypes, may add to the complexity of genetic determinants of prion disease susceptibility.     

Interaction of Peptide Aptamers with Prion Protein Central Domain Promotes α-Cleavage of PrP<Superscript>C</Superscript>

Prion diseases are infectious and fatal neurodegenerative diseases affecting humans and animals. Transmission is possible within and between species with zoonotic potential. Currently, no prophylaxis or treatment exists. Prions are composed of the misfolded isoform PrP^Sc of the cellular prion protein PrP^C. Expression of PrP^C is a prerequisite for prion infection, and conformational conversion of PrP^C is induced upon its direct interaction with PrP^Sc. Inhibition of this interaction can abrogate prion propagation, and we have previously established peptide aptamers (PAs) binding to PrP^C as new anti-prion compounds. Here, we mapped the interaction site of PA8 in PrP and modeled the complex in silico to design targeted mutations in PA8 which presumably enhance binding properties. Using these PA8 variants, we could improve PA-mediated inhibition of PrP^Sc replication and de novo infection of neuronal cells. Furthermore, we demonstrate that binding of PA8 and its variants increases PrP^C α-cleavage and interferes with its internalization. This gives rise to high levels of the membrane-anchored PrP-C1 fragment, a transdominant negative inhibitor of prion replication. PA8 and its variants interact with PrP^C at its central and most highly conserved domain, a region which is crucial for prion conversion and facilitates toxic signaling of Aβ oligomers characteristic for Alzheimer’s disease. Our strategy allows for the first time to induce α-cleavage, which occurs within this central domain, independent of targeting the responsible protease. Therefore, interaction of PAs with PrP^C and enhancement of α-cleavage represent mechanisms that can be beneficial for the treatment of prion and other neurodegenerative diseases.     

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP^C) to a misfolded pathogenic conformer (PrP^Sc). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP^Sc. Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP^Sc particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP^Sc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP^Sc conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP^Sc. Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.     

Insoluble cellular prion protein and its association with prion and Alzheimer diseases

The soluble cellular prion protein (PrP^C) is best known for its association with prion disease (PrD) through its conversion to a pathogenic insoluble isoform (PrP^Sc). However, its deleterious effects independent of PrP^Sc have recently been observed not only in PrD but also in Alzheimer disease (AD), two diseases which mainly affect cognition. At the same time, PrP^C itself seems to have broad physiologic functions including involvement in cognitive processes. The PrP^C that is believed to be soluble and monomeric has so far been the only PrP conformer observed in the uninfected brain. In 2006, we identified an insoluble PrP^C conformer (termed iPrP^C) in uninfected human and animal brains. Remarkably, the PrP^Sc-like iPrP^C shares the immunoreactivity behavior and fragmentation with a newly-identified PrP^Sc species in a novel human PrD termed variably protease-sensitive prionopathy. Moreover, iPrP^C has been observed as the major PrP species that interacts with amyloid β (Aβ) in AD. This article highlights evidence of PrP involvement in two putatively beneficial and deleterious PrP-implicated pathways in cognition and hypothesizes first, that beneficial and deleterious effects of PrP^C are attributable to the chameleon-like conformation of the protein and second, that the iPrP^C conformer is associated with PrD and AD.Key words: prion protein, prion disease, cognition, cognitive deficit, insoluble prion protein, Alzheimer disease, variably protease-sensitive prionopathy, dementia, memory     

Potential approaches for heterologous prion protein treatment of prion diseases

Prion diseases, or transmissible spongiform encephalopathies (TSEs) are progressive, fatal neurodegenerative diseases with no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrP^C) into a protease resistant infectious form (PrP^res). The efficiency of this conversion is predicated upon a number of factors, most notably a strong homology between cellular PrP^C and PrP^res. In our recently published study, we infected mice with the RML-Chandler strain of scrapie and treated them with heterologous hamster prion proteins. This treatment was seen to reduce clinical signs of prion disease, to delay the onset of clinical symptoms and to prolong survival. In this current article we discuss potential mechanisms of action of treatment with heterologous prion proteins. We also discuss potential extensions of these studies using a heterologous rabbit PrP-based treatment strategy or a peptide based strategy, and improvement of treatment delivery including a lentiviral-based system.     

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

Prion diseases are caused by a conformational modification of the cellular prion protein (PrP^C) into disease-specific forms, termed PrP^Sc, that have the ability to interact with PrP^C promoting its conversion to PrP^Sc. In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP^C region involved in the interaction with PrP^Sc thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP^Sc in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding.     

Molecular dynamics studies on the buffalo prion protein

It was reported that buffalo is a low susceptibility species resisting to transmissible spongiform encephalopathies (TSEs) (same as rabbits, horses, and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (except for rabbits, dogs, horses, and buffalo), manifesting as scrapie in sheep and goats; bovine spongiform encephalopathy (BSE or “mad–cow” disease) in cattle; chronic wasting disease in deer and elk; and Creutzfeldt–Jakob diseases, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, and Kulu in humans etc. In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP^C), predominantly with α-helices, into insoluble abnormally folded infectious prions (PrP^Sc), rich in β-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrP^C (BufPrP^C), in order to understand the reason why buffalo is resistant to prion diseases. We first did molecular modeling of a homology structure constructed by one mutation at residue 143 from the NMR structure of bovine and cattle PrP(124–227); immediately we found that for BufPrP^C(124–227), there are five hydrogen bonds (HBs) at Asn143, but at this position, bovine/cattle do not have such HBs. Same as that of rabbits, dogs, or horses, our molecular dynamics studies also revealed there is a strong salt bridge (SB) ASP178–ARG164 (O–N) keeping the β2–α2 loop linked in buffalo. We also found there is a very strong HB SER170–TYR218 linking this loop with the C-terminal end of α-helix H3. Other information, such as (i) there is a very strong SB HIS187–ARG156 (N–O) linking α-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrP^C will be exposed (L.H. Zhong (2010). Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. Journal of Biomolecular Structure and Dynamics 28(3), 355–361)), (ii) at D178, there is a HB Y169–D178 and a polar contact R164–D178 for BufPrP^C instead of a polar contact Q168–D178 for bovine PrP^C (C.J. Cheng, & V. Daggett. (2014). Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4(1), 181–201), (iii) BufPrP^C owns three 3₁₀ helices at 125–127, 152–156, and in the β2–α2 loop, respectively, and (iv) in the β2–α2 loop, there is a strong π–π stacking and a strong π–cation F175–Y169–R164.(N)NH2, has been discovered.     

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

Prion diseases are caused by a conformational modification of the cellular prion protein (PrP^C) into disease-specific forms, termed PrP^Sc, that have the ability to interact with PrP^C promoting its conversion to PrP^Sc. In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP^C region involved in the interaction with PrP^Sc thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP^Sc in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding.     

α-Cleavage of cellular prion protein

The cellular prion protein (PrP^C) is subjected to various processing under physiological and pathological conditions, of which the α-cleavage within the central hydrophobic domain not only disrupts a region critical for both PrP toxicity and PrP^C to PrP^Sc conversion but also produces the N1 fragment that is neuroprotective and the C1 fragment that enhances the pro-apoptotic effect of staurosporine in one report and inhibits prion in another. The proteases responsible for the α-cleavage of PrP^C are controversial. The effect of ADAM10, ADAM17, and ADAM9 on N1 secretion clearly indicates their involvement in the α-cleavage of PrP^C, but there has been no report of direct PrP^C α-cleavage activity with any of the three ADAMs in a purified protein form. We demonstrated that, in muscle cells, ADAM8 is the primary protease for the α-cleavage of PrP^C, but another unidentified protease(s) must also play a minor role. We also found that PrP^C regulates ADAM8 expression, suggesting that a close examination on the relationships between PrP^C and its processing enzymes may reveal novel roles and underlying mechanisms for PrP^C in non-prion diseases such as asthma and cancer.     

��-Cleavage of cellular prion protein

The cellular prion protein (PrP^C) is subjected to various processing under physiological and pathological conditions, of which the α-cleavage within the central hydrophobic domain not only disrupts a region critical for both PrP toxicity and PrP^C to PrP^Sc conversion but also produces the N1 fragment that is neuroprotective and the C1 fragment that enhances the pro-apoptotic effect of staurosporine in one report and inhibits prion in another. The proteases responsible for the α-cleavage of PrP^C are controversial. The effect of ADAM10, ADAM17, and ADAM9 on N1 secretion clearly indicates their involvement in the α-cleavage of PrP^C, but there has been no report of direct PrP^C α-cleavage activity with any of the three ADAMs in a purified protein form. We demonstrated that, in muscle cells, ADAM8 is the primary protease for the α-cleavage of PrP^C, but another unidentified protease(s) must also play a minor role. We also found that PrP^C regulates ADAM8 expression, suggesting that a close examination on the relationships between PrP^C and its processing enzymes may reveal novel roles and underlying mechanisms for PrP^C in non-prion diseases such as asthma and cancer.     

Microdeletions within the hydrophobic core region of cellular prion protein alter its topology and metabolism

The cellular prion protein (PrP^C) is a GPI-anchored cell-surface protein. A small subset of PrP^C molecules, however, can be integrated into the ER-membrane via a transmembrane domain (TM), which also harbors the most highly conserved regions of PrP^C, termed the hydrophobic core (HC). A mutation in HC is associated with prion disease resulting in an enhanced formation of a transmembrane form (^CtmPrP), which has thus been postulated to be a neurotoxic molecule besides PrP^Sc. To elucidate a possible physiological function of the transmembrane domain, we created a set of mutants carrying microdeletions of 2-8 aminoacids within HC between position 114 and 121. Here, we show that these mutations display reduced propensity for transmembrane topology. In addition, the mutants exhibited alterations in the formation of the C1 proteolytic fragment, which is generated by α-cleavage during normal PrP^C metabolism, indicating that HC might function as recognition site for the protease(s) responsible for PrP^C α-cleavage. Interestingly, the mutant G113V, corresponding to a hereditary form of prion disease in humans, displayed increased ^CtmPrP topology and decreased α-cleavage in our in vitro assay. In conclusion, HC represents an essential determinant for transmembrane PrP topology, whereas the high evolutionary conservation of this region is rather based upon preservation of PrP^C α-cleavage, thus highlighting the biological importance of this cleavage.     

A systems approach to prion disease

Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrP^C) to disease‐causing PrP^Sc isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrP^Sc replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches.     

Homodimerization as a molecular switch between low and high efficiency PrPC cell surface delivery and neuroprotective activity

PrP^C is associated with a variety of functions, and its ability to interact with a multitude of partners, including itself, may largely explain PrP multifunctionality and the lack of consensus on the genuine physiological function of the protein in vivo. In contrast, there is a consensus in the literature that alterations in PrP^C trafficking and intracellular retention result in neuronal degeneration. In addition, a proteolytic modification in the late secretory pathway termed the α-cleavage induces the secretion of PrPN1, a PrP^C-derived metabolite with fascinating neuroprotective activity against toxic oligomeric Aβ molecules implicated in Alzheimer disease. Thus, studies focusing on understanding the regulation of PrP^C trafficking to the cell surface and the modulation of α-cleavage are essential. The objective of this commentary is to highlight recent evidences that PrP^C homodimerization stimulates trafficking of the protein to the cell surface and results in high levels of PrPN1 secretion. We also discuss a hypothetical model for these results and comment on future challenges and opportunities.