BBA - Molecular Basis of Disease (v.1772, #6)

Special issue: Prion-related disorders by Glenn C. Telling (597).

Update on human prion disease by Jonathan D.F. Wadsworth; John Collinge (598-609).
The recognition that variant Creutzfeldt–Jakob disease (vCJD) is caused by the same prion strain as bovine spongiform encephalopathy in cattle has dramatically highlighted the need for a precise understanding of the molecular biology of human prion diseases. Detailed clinical, pathological and molecular data from a large number of human prion disease patients indicate that phenotypic diversity in human prion disease relates in part to the propagation of disease-related PrP isoforms with distinct physicochemical properties. Incubation periods of prion infection in humans can exceed 50 years and therefore it will be some years before the extent of any human vCJD epidemic can be predicted with confidence.
Keywords: Bovine spongiform encephalopathy; Creutzfeldt-Jakob disease; Fatal familial insomnia; Gerstmann-Sträussler-Scheinker disease; Kuru; Prion; Prion disease; Prion protein; Transmissible spongiform encephalopathy; Variant Creutzfeldt-Jakob disease;

Chronic wasting disease by Christina J. Sigurdson; Adriano Aguzzi (610-618).
Until recently, chronic wasting disease of cervids, the only prion disease affecting wildlife, was believed to be geographically concentrated to Colorado and Wyoming within the United States. However, increased surveillance has unveiled several additional pockets of CWD-infected deer and elk in 12 additional states and 2 Canadian provinces. Deer and elk with CWD have extensive aggregates of PrPSc not only in the central nervous system, but also in peripheral lymphoid tissues, skeletal muscle, and other organs, perhaps influencing prion shedding. Indeed, CWD is transmitted efficiently among animals by horizontal routes, although the mechanism of spread is unknown. Genetic polymorphisms in the Prnp gene may affect CWD susceptibility, particularly at codon 225 (S/F) in deer and codon 132 (M/L) in elk. Since CWD infects free-ranging animals and is efficiently spread, disease management will be a challenge.
Keywords: CWD; Deer; Elk; Prion; TSE; Review;

The study of the biology of scrapie in sheep is irretrievably associated with the genetics of the PrP gene in sheep. Control of susceptibility and resistance is so closely linked to certain alleles of the sheep PrP gene that no review on scrapie can avoid PrP genetics. Before the importance of PrP protein was discovered and before the influence of the gene itself on disease incidence was understood, it was clear there were some sheep which were more susceptible to natural scrapie than others and that this feature was heritable. These early observations have led to the development and use of PrP genotyping in sheep in what is probably the biggest genetic selection process ever attempted. The accompanying increase in surveillance has also discovered a novel type of scrapie, the subject of much speculation about its origin.
Keywords: Natural scrapie; Atypical scrapie; Sheep; PrP genetics; Susceptibility; Resistance;

The cellular prion protein (PrPC): Its physiological function and role in disease by Laura Westergard; Heather M. Christensen; David A. Harris (629-644).
Prion diseases are caused by conversion of a normal cell-surface glycoprotein (PrPC) into a conformationally altered isoform (PrPSc) that is infectious in the absence of nucleic acid. Although a great deal has been learned about PrPSc and its role in prion propagation, much less is known about the physiological function of PrPC. In this review, we will summarize some of the major proposed functions for PrPC, including protection against apoptotic and oxidative stress, cellular uptake or binding of copper ions, transmembrane signaling, formation and maintenance of synapses, and adhesion to the extracellular matrix. We will also outline how loss or subversion of the cytoprotective or neuronal survival activities of PrPC might contribute to the pathogenesis of prion diseases, and how similar mechanisms are probably operative in other neurodegenerative disorders.
Keywords: Prion; Neurodegeneration; Apoptosis; Oxidative stress; Copper; Bax;

It has been difficult to reconcile the absence of pathology and apparently normal behavior of mice lacking prion protein (PrP), referred to as Prnp 0/0 mice, with a mechanism of prion pathogenesis involving progressive loss of PrPC-mediated neuroprotection. However, here we report that Prnp 0/0 mice exhibit significant age-related defects in motor coordination and balance compared with mice expressing wild type Prnp on a syngeneic background, and that the brains of behaviorally-impaired Prnp 0/0 mice display the cardinal neuropathological hallmarks of spongiform pathology and reactive astrocytic gliosis that normally accompany prion disease. Consistent with the appearance of cerebellar ataxia as an early symptom in patients with Gerstmann–Sträussler–Scheinker syndrome (GSS), an inherited form of human prion disease, motor coordination and balance defects manifested in a transgenic (Tg) mouse model of GSS considerably earlier than the onset of end-stage neurodegenerative disease. Our results are consistent with a mechanism in which loss of normal PrPC function is an important pathological component of prion diseases.
Keywords: Prion; Spongiform degeneration; PrPC neuroprotection;

The prion protein family: Diversity, rivalry, and dysfunction by Joel C. Watts; David Westaway (654-672).
The prion gene family currently consists of three members: Prnp which encodes PrPC, the precursor to prion disease associated isoforms such as PrPSc; Prnd which encodes Doppel, a testis-specific protein involved in the male reproductive system; and Sprn which encodes the newest PrP-like protein, Shadoo, which is expressed in the CNS. Although the identification of numerous candidate binding partners for PrPC has hinted at possible cellular roles, molecular interpretations of PrPC activity remain obscure and no widely-accepted view as to PrPC function has emerged. Nonetheless, studies into the functional interrelationships of prion proteins have revealed an interesting phenomenon: Doppel is neurotoxic to cerebellar cells in a manner which can be blocked by either PrPC or Shadoo. Further examination of this paradigm may help to shed light on two prominent unanswered questions in prion biology: the functional role of PrPC and the neurotoxic pathways initiated by PrPSc in prion disease.
Keywords: Prion; PrP; Doppel; Shadoo; Neurodegenerative disease; Transgenic mice; Knockout mice; Binding partners; Neurotoxicity;

The role of host PrP in Transmissible Spongiform Encephalopathies by Enrico Cancellotti; Rona M. Barron; Matthew T. Bishop; Patricia Hart; Frances Wiseman; Jean C. Manson (673-680).
PrP has a central role in the Transmissible Spongiform Encephalopathies (TSEs), and mutations and polymorphisms in host PrP can profoundly alter the host's susceptibility to a TSE agent. However, precisely how host PrP influences the outcome of disease has not been established. To investigate this we have produced by gene targeting a series of inbred lines of transgenic mice expressing different PrP genes. This allows us to study directly the influence of the host PrP gene in TSEs. We have examined the role of glycosylation, point mutations, polymorphisms and PrP from different species on host susceptibility and the disease process both within the murine species and across species barriers.
Keywords: PrP; Prions; Gene targeting; Transgenic mice; Point mutations; Infection;

The prion strain phenomenon: Molecular basis and unprecedented features by Rodrigo Morales; Karim Abid; Claudio Soto (681-691).
Prions are unconventional infectious agents responsible for transmissible spongiform encephalopathies. Compelling evidences indicate that prions are composed exclusively by a misfolded form of the prion protein (PrPSc) that replicates in the absence of nucleic acids. One of the most challenging problems for the prion hypothesis is the existence of different strains of the infectious agent. Prion strains have been characterized in most of the species. Biochemical characteristics of PrPSc used to identify each strain include glycosylation profile, electrophoretic mobility, protease resistance, and sedimentation. In vivo, prion strains can be differentiated by the clinical signs, incubation period after inoculation and the lesion profiles in the brain of affected animals. Sources of prion strain diversity are the inherent conformational flexibility of the prion protein, the presence of PrP polymorphisms and inter-species transmissibility. The existence of the strain phenomenon is not only a scientific challenge, but it also represents a serious risk for public health. The dynamic nature and inter-relations between strains and the potential for the generation of a large number of new prion strains is the perfect recipe for the emergence of extremely dangerous new infectious agents.
Keywords: Prions; Prion strains; Protein misfolding; Scrapie; Creutzfeldt-Jakob disease;

Converting the prion protein: What makes the protein infectious by Ilia V. Baskakov; Leonid Breydo (692-703).
The discovery of prion disease transmission in mammals, as well as a non-Mendelian type of inheritance in yeast, has led to the establishment of a new concept in biology, the prion hypothesis. The prion hypothesis postulates that an abnormal protein conformation propagates itself in an autocatalytic manner via recruitment of the normal isoform of the same protein as a substrate, and thereby acts either as a transmissible agent of disease (in mammals) or as a heritable determinant of phenotype (in yeast and fungus). Although reconstitution of fully infectious PrPSc in vitro from synthetic components has not yet been achieved, numerous lines of evidence indicate that the prion protein is the major and essential component, if not the only one, of the prion infectious agent. This article summarizes our current knowledge about the chemical nature of the prion infectious agent, describes potential strategies and challenges related to the generation of prion infectivity de novo, proposes new hypotheses to explain the apparently low infectivity observed in the first synthetic mammalian prions, and describes plausible effects of chemical modifications on prion conversion.
Keywords: Prion protein; Amyloid fibril; Synthetic prion; In vitro conversion; Transmission barrier; Prion infectivity;

Prion diseases are characterised by the conversion of a cellular prion protein (PrPC) by its misfolded, hence pathogenic, isoform (PrPSc). The efficiency of this transition depends on the molecular similarities between both interaction partners and on the intrinsic convertibility of PrPC. Transgenic mice expressing chimeric murine/ovine PrPC (Tgmushp mice) are susceptible to BSE and/or scrapie prions of bovine or ovine origin while transgenic mice expressing similar murine/bovine PrPC chimera (Tgmubo mice) are essentially resistant. We have studied this phenomenon by cell-free conversion on procaryotically expressed chimeric PrPC. Mouse passaged scrapie or BSE PrPSc was used as a seed and the conversion reaction was carried out under semi-native conditions. The results obtained in this assay were similar to those of our in vivo experiments. Since mubo- and mushp-PrPC differ only at four amino acid positions (S96G, N142S, Y154H and Q185E), single or double point mutations of mushp-PrPC were examined in the cell-free conversion assay. While the scrapie Me7 prion induced conversion was largely reduced by the N142S and Q185E but not by the S96G and Y154H mutation, the BSE induced conversion was retained in all mutants. Newly formed PrPres exhibited strain specific characteristics, such as the localisation of the proteinase K cleavage site, even in the chimeric PrPC mutants. We therefore postulate that the efficiency of the conversion of chimeric PrPC depends on the amino acid sequence as well as on prion strain specific effects.
Keywords: Prion; BSE; Scrapie; Conversion; Species barrier;