Curr. Issues Mol. Biol., Volume 12, Issue 2 (July 2010) – 7 articles

There are two central phenomena in prion disease: prion replication and prion neurotoxicity. Underlying them both is the conversion of a host-encoded ubiquitously expressed protein, prion protein (PrP^C), into a partially-protease resistant isoform, PrP^Sc, which accumulates in the brain. PrP^Sc is associated with both pathology and infectivity. In the absence of PrP^C, PrP^Sc cannot be generated and PrP-null mice do not propagate infectivity or develop pathology on infection with scrapie. However, while PrP^C expression is fundamental to both prion infectivity and neurodegeneration, the uncoupling of these processes is a growing concept in the field. This dissociation is evident in subclinical states of prion infection, where PrP^Sc levels are high in the absence of disease, and in transgenic mice experiments, where, despite extra-neuronal PrP^Sc accumulation, even in very high amounts, there is no neurotoxicity. Both these models have further implications. Thus depleting PrP^C from neurons (but not glia) of prion-infected mice prevents clinical disease, and detaching it from the surface of cells by removing its anchor does the same. The uncoupling toxicity and infectivity has implications for the nature of the neurotoxic species; these mouse models suggest that the site for the generation of this species is intra-neuronal. This review considers the role of neuronal surface-expressed PrP^C in mediating toxicity in prion infection, and the dissociation of this from the deposition of PrP^Sc. Full article

Prion diseases are characterized by the conformational transition of the cellular prion protein (PrP^C) into an aberrant protein conformer, designated scrapie-prion protein (PrP^Sc). A causal link between protein misfolding and neurodegeneration has been established for a variety of neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease and polyglutamine diseases, but there is an ongoing debate about the nature of the neurotoxic species and how non-native conformers can damage neuronal populations. PrP is normally imported into the endoplasmic reticulum (ER) and targeted to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. However, several conditions, such as ER stress or some pathogenic mutations in the PrP gene, can induce the mislocalization of PrP in the cytosol, where it has a neurotoxic potential as demonstrated in cell culture and transgenic mouse models. In this review we focus on intrinsic factors and cellular pathways implicated in the import of PrP into the ER and its mistargeting to the cytosol. The findings summarized here not only reveal a complex regulation of the biogenesis of PrP, but also provide interesting new insight into toxic activities of pathogenic protein conformers and quality control pathways of ER-targeted proteins. Full article

Metal induced free radicals are important mediators of neurotoxicity in several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Similar evidence is now emerging for prion diseases, a group of neurodegenerative disorders of humans and animals. The main pathogenic agent in all prion disorders is PrP-scrapie (PrP^Sc), a beta-sheet rich isoform of a normal cell surface glycoprotein known as the prion protein (PrP^C). Deposits of PrP^Sc in the brain parenchyma are believed to induce neurotoxicity through poorly understood mechanisms. Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrP^Sc-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrP^C in metal metabolism, and loss of this function due to aggregation to the disease associated PrP^Sc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrP^Sc due to sequestration of PrP^C-associated metals within the aggregates, resulting in the generation of redox-active PrP^Sc complexes. The physiological implications of some PrP^C-metal interactions are known, while others are still unclear. The pathological implications of PrP^C-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrP^C to a PrP^Sc-like form. Despite its significance, only limited information is available on PrP-metal interaction and its implications on prion disease pathogenesis. In this review, we summarize the physiological significance and pathological implications of PrP-metal interaction on prion disease pathogenesis. Full article

Prion diseases are infectious and fatal neurodegenerative disorders of man and animals which are characterized by spongiform degeneration in the central nervous system. Prion propagation involves the endocytic pathway and endosomal and lysosomal compartments are implicated in trafficking and re-cycling as well as final degradation of prions. Shifting the equilibrium between propagation and lysosomal clearance to the latter impairs cellular prion load. This and earlier findings of autophagic vacuoles in correlation to prion infections both in in vitro and in vivo studies prompted us and others to analyze the role of autophagy in prion infection. Autophagy is a fundamental cellular bulk degradation process for e.g. organelles or cytoplasmic proteins which has many implications for physiology and patho-physiology of cells and whole organisms. In various neurodegenerative disease models mainly protective functions of autophagy were recently described. In this review, we focus on recent findings which correlate autophagy and its manipulations with prion infection scenarios, and discuss perspectives and future directions. The findings summarized here add to the knowledge of the role of autophagy in neurodegeneration and provide interesting new insight into how non-cytosolic aggregated proteins might be subjected to autophagic clearance. Full article

PrP^C is highly expressed in both the central and peripheral nervous systems from early stages of development and in adulthood. Its major conformational change and conversion into an abnormal form (PrP^Sc) has been associated with the generation of prions, the infectious agent of transmissible spongiform encephalopathies (TSEs). The massive neurodegeneration presented by individuals suffering from these diseases has been associated with the gain of neurotoxic activity of PrP^Sc. On the other hand, major neurodegeneration is also observed in transgenic mice expressing PrP^C molecules deleted of specific domains, which points to important functional domains within this molecule, and supports the hypothesis that loss-of PrP^C function may contribute to the pathogenesis of TSEs. Furthermore, a large body of data demonstrates direct or indirect interaction of PrP^C with extracellular matrix proteins, soluble factors, transmembrane proteins, G-protein coupled receptors and ions channels. The ability of PrP^C to drive the assembly of multi-component complexes at the cell surface is likely the basis for its neurotrophic functions. These properties indicate that PrP^C may be relevant for not only the spongiform encephalophaties, but also as an ancillary component of the pathogenesis of other neurodegenerative diseases, and therefore amenable to therapeutic targeting. Full article

The chemical nature of prions and the mechanism by which they propagate are now reasonably well understood. In contrast, much less is known about the identity of the toxic prion protein (PrP) species that are responsible for neuronal death, and the cellular pathways that these forms activate. In addition, the normal, physiological function of cellular PrP (PrP^C) has remained mysterious, hampering efforts to determine whether loss or alteration of this function contributes to the disease phenotype. Considerable evidence now suggests that aggregation, toxicity, and infectivity are distinct properties of PrP that do no necessarily coincide. In this review, we will discuss several mutant forms of PrP that produce spontaneous neurodegeneration in humans and/or transgenic mice without the formation of infectious PrP^Sc. These include an octapeptide insertional mutation, point mutations that favor synthesis of transmembrane forms of PrP, and deletions encompassing the central domain whose neurotoxicity is antagonized by the presence of wild-type PrP. By isolating the neurotoxic effects of PrP from the formation of infectious prions, these mutants have provided important insights into possible pathogenic mechanisms. These studies suggest that prion neurotoxicity may involve subversion of a cytoprotective activity of PrP^C via altered signaling events at the plasma membrane. Full article

A conformational transition of the cellular prion protein (PrP^C) into an aberrantly folded isoform designated scrapie prion protein (PrP^Sc) is the hallmark of a variety of neurodegenerative disorders collectively called prion diseases. They include Creutzfeldt-Jakob disease and Gerstmann-Stäussler-Scheinker syndrome in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer. In contrast to the deadly properties of misfolded PrP, PrP^C seems to possess a neuroprotective activity. More-over, animal models indicated that the stress-protective activity of PrP^C and the neurotoxic effects of PrP^Sc are somehow interconnected. In this special issue of Current Issues in Molecular Biology we have assembled a set of reviews from some leading scientists in the field to highlight the apparently incongruous activities of different PrP conformers. The articles will outline current research on celluar pathways implicated in the formation and signaling of neurotoxic and physiological PrP isoforms and delineate future research direction. Vilma Martins comments on our current understanding about the physiologcial activity of PrP^C and its possible role as a neurotrophic factor. The observation that aberrant PrP conformers can cause neurodegeneration in the absence of infectious prion propagation is an expanding field highlighted by David Harris. Giovanna Mallucci expands on this topic and reports on the intriguing finding that the GPI anchor of PrP^C is required to mediate neurotoxic effects of scrapie prions.To follow up this track, Konstanze Winklhofer and I specifically concentrate on pathways implicated in the formation and neurotoxic properties of cytosolically localized PrP. Neena Singh illustrates that metal ions can have a significant impact on the processing of PrP. Finally, Hermann Schätzl provides insight into the role of autophagy in the propagation and clearance of PrP^Sc. I am grateful to all contributing authors and editorial staff for their time and efforts to prepare this special issue. Full article