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The challenge of biology and medicine in the 21st century is complexity. A paradigm change that is currently emerging is the idea that biology is an informational science and that biological information is mediated by dynamic biological networks. The systems approach to biology and medicine is a general category of approaches that appear to be very effective in dealing with biological complexity. It requires a cross-disciplinary environment and the effective integration of biology, technology and computation/mathematics. I will discuss my view of systems biology. Then I will discuss a systems approach to disease and demonstrate how it profoundly alters our view of medicine. This approach is centered on the simple ideal that disease arises from disease-perturbed biological networks and that the dynamically altered patterns of information expressed explain the pathophysiology of disease. Moreover, they open new systems approaches to diagnostics and therapy. I will discuss prion infection in mice as an example of a systems approach to disease and I will discuss the implications these observations have for diagnosis and therapy. My prediction is that our current largely reactive medicine will be largely replaced with predictive, preventive, personalized and participatory (P4) medicine over the next 10 to 20 years.

Neuropathological, epidemiological and experimental data indicate a potential interrelationship between Alzheimer's disease and prion diseases. Proteolytic processing of amyloid precursor protein (APP) by beta-secretase was recently suggested to be controlled by prion protein expression. Here, we characterized the prion infection of Tg2576 mice, which overexpress the human APP(Swe) protein. Prion infection of Tg2576-mice led to an early death of the animals, which was preceded by a relatively short symptomatic stage. However, disease-associated gliosis and deposition of misfolded prion protein PrP(Sc) were identical in infected Tg2576-mice and non-transgenic littermate controls. To analyze the effect of prion infection on APP processing and generation of beta-amyloid we determined cortical levels of SDS- and formic acid (FA)-extractable forms of beta-amyloid (1-40) and (1-42) by ELISA. Formic acid-extractable Abeta (1-42) levels were 10-fold higher in infected versus uninfected Tg2576 mice whereas other forms of Abeta were essentially unaffected by the prion infection. Hence, the experimental model demonstrates that a prion infection of the CNS promotes selectively formation of FA-extractable Abeta(1-42) in Tg2576 mice.

The expression of the prion protein (PrP) is essential for transmissible spongiform encephalopathy (TSE) or prion diseases to occur, but the underlying mechanism of infection remains unresolved. To address the hypothesis that glycosylation of host PrP is a major factor influencing TSE infection, we have inoculated gene-targeted transgenic mice that have restricted N-linked glycosylation of PrP with three TSE strains. We have uniquely demonstrated that mice expressing only unglycosylated PrP can sustain a TSE infection, despite altered cellular location of the host PrP. Moreover we have shown that brain material from mice infected with TSE that have only unglycosylated PrPSc is capable of transmitting infection to wild-type mice, demonstrating that glycosylation of PrP is not essential for establishing infection within a host or for transmitting TSE infectivity to a new host. We have further dissected the requirement of each glycosylation site and have shown that different TSE strains have dramatically different requirements for each of the glycosylation sites of host PrP, and moreover, we have shown that the host PrP has a major role in determining the glycosylation state of de novo generated PrPSc., Author Summary In prion infection, disease requires the presence of the endogenous host-encoded prion protein, PrP. PrP is a glycoprotein (modified by the addition of sugar molecules) with two consensus sites for sugars to attach. Different PrP forms are usually observed: one diglycosylated, two different monoglycosylated, and one unglycosylated. How PrP glycosylation influences prion infection remains obscure. We have used three different murine transgenic models, developed with the gene-replacement technique, to investigate each glycotype of PrP contribution to prion diseases, or transmissible spongiform encephalopathies (TSEs). For this purpose, mice expressing mono- or unglycosylated PrP were challenged with different prion strains. Remarkably, we found that glycosylation of host PrP is not mandatory for TSE infection, because mice expressing only unglycosylated PrP were susceptible to infection and able to transmit the disease to other animals. However, we also show that host PrP glycosylation can modulate the infectious process, since strains differ in their ability to infect hosts with restricted PrP glycosylation. These results elucidate the role of glycosylation in prion infection and in particular demonstrate that strains need sugars at specific sites of host PrP to successfully induce prion disease., The primary determinant of the prion infectious process is the glycosylation status of the host prion protein, PrP.

Nucleic acids catalyse the conversion of alpha-helical prion protein to the beta-structured protein oligomers and amyloids structurally similar to the infectious isoform of protein. Simultaneously, the prion protein, similar to gene regulating proteins, bends, unwinds and condenses nucleic acid. These properties might be related to the biological function and prion infection.

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.

Cell models for prion diseases are mainly of neuronal origin. However, the pathological isoform PrP(Sc) of cellular prion protein (PrP(c)) and prion infectivity are found in a variety of extraneural tissues in prion diseases. Although many cell types are not able to propagate PrP(Sc), little is known about cellular mechanism counteracting prion infection. It is desirable to identify neuronal or non-neuronal cell models that restrict PrP(Sc) generation or propagate PrP(Sc) only transiently. Neuroendocrine cells are derived from tumours forming the interface between endocrine and nervous system. We investigated the susceptibility of such murine cell lines to prion infection, which were in principle able to transiently propagate PrP(Sc). Surprisingly and in contrast to neuronal cells prion infection was abrogated by rapid and PrP(Sc)-specific down-regulation of PrP(c) expression upon exposure to prion-infected material. Cell lines described here provide novel models for studying PrP(c) regulation and intrinsic cellular defence mechanisms upon prion exposure.

Transmissible spongiform encephalopaties (TSEs) or prion diseases develop as central nervous system (CNS) disorders characterized by extremely long incubation periods. Although TSEs do not go along with inflammatory infiltrates and/or antibody production against the prion protein (PrPSc), the immune system plays an important role in pathogenesis as long as different lymphoid organs (Peyer's patches, lymph nodes and spleen) may facilitate the accumulation and further spread of prions after peripheral exposure. In this work we investigated the changes in lymphoid and dendritic cell (DC) populations as well as the implications of different cytokines during disease progression after experimental oral inoculation of prions in a transgenic mouse model. At different days post-inoculation (dpi), T and B lymphocytes and DC populations from lymphoid organs, blood and brain were analyzed by flow cytometry and immunohistochemistry. Besides time related variations in lymphoid cell numbers due to the aging of the animals significant changes related with the infection were found in mesenteric lymph nodes, peripheral blood leukocytes (PBLs) as well as in spleen, affecting the CD4/CD8 ratio. In contrast, little or no variation was detected in Peyer's Patches or in thymus either associated with aging or the infection status. At individual time points significant differences between infected and control mice were seen in the CD8, CD4 and DC populations, with less evidence of differences in the B cell compartment. Finally, a pro-inflammatory phenotype occurred at early times in the spleen, where the levels of lymphotoxin-β mRNA were found augmented with respect to controls. Altogether, these results suggest that normal regulation of lymphocyte populations becomes altered along the progression of a prion infection. © 2007 Elsevier B.V. All rights reserved.

Cell culture systems represent a crucial part in basic prion research; yet, cell lines that are susceptible to prions, especially to field isolated prions that were not adapted to rodents, are very rare. The purpose of this study was to identify and characterize a cell line that was susceptible to ruminant-derived prions and to establish a stable prion infection within it. Based on species and tissue of origin as well as PrP expression rate, we pre-selected a total of 33 cell lines that were then challenged with natural and with mouse propagated BSE or scrapie inocula. Here, we report the successful infection of a non-transgenic bovine cell line, a sub-line of the bovine kidney cell line MDBK, with natural sheep scrapie prions. This cell line retained the scrapie infection for more than 200 passages. Selective cloning resulted in cell populations with increased accumulation of PrPres, although this treatment was not mandatory for retaining the infection. The infection remained stable, even under suboptimal culture conditions. The resulting infectivity of the cells was confirmed by mouse bioassay (Tgbov mice, Tgshp mice). We believe that PES cells used together with other prion permissive cell lines will prove a valuable tool for ongoing efforts to understand and defeat prions and prion diseases.

Prion diseases, including scrapie, are incurable neurodegenerative disorders. Some compounds can delay disease after a peripheral scrapie inoculation, but few are effective against advanced disease. Here, we tested multiple related porphyrins, but only Fe(III)meso-tetra(4-sulfonatophenyl)porphine injected into mouse brains after intracerebral scrapie inoculation substantially increased survival times.

Using permissive cell lines of epithelial or neuroglial origin, we found that scratch-wounding a small proportion of the recipient cells prior to prion exposure strongly reduced the cell culture's susceptibility to infection. We provide evidence suggesting that wound-triggered inhibition of prion infection was mediated by the release of nucleotides in the extracellular medium of injured cultures. While cell wounding or ATP treatment of unwounded target cells inhibited de novo infection, we found that they had no effect on steady-state infected cultures, indicating that these treatments affect the early stages of infection. These findings support the view that cells have the capacity to modulate their permissiveness to prion infection in response to external stimuli, such as a signalling molecule.

Variant Creutzfeldt-Jakob disease (CJD) is thought to be caused by dietary or other exposure to bovine spongiform encephalopathy (BSE) prions. The prevalence of preclinical or subclinical prion infection in the UK is currently unknown. Since clinical variant CJD is uniformly associated with tonsillar prion infection, we screened 2000 anonymous surgical tonsillectomy specimens for disease-associated prion protein. Analysis by both high sensitivity immunoblotting and immunohistochemistry detected no positive cases. However, this negative result cannot provide reassurance that relevant community infection is unlikely because of the fairly small sample size, demographic and age-related factors, and unknown test sensitivity during the prolonged incubation period. Nevertheless, our findings establish a protocol for prevalence screening on a national scale.

Distinct prion strains can be distinguished by differences in incubation period, neuropathology and biochemical properties of disease-associated prion protein (PrPSc) in inoculated mice. Reliable comparisons of mouse prion strain properties can only be achieved after passage in genetically identical mice, as host prion protein sequence and genetic background are known to modulate prion disease phenotypes. While multiple prion strains have been identified in sheep scrapie and Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (BSE) is thought to be caused by a single prion strain. Primary passage of BSE prions to different lines of inbred mice resulted in the propagation of two distinct PrPSc types, suggesting that two prion strains may have been isolated. To investigate this further, these isolates were subpassaged in a single line of inbred mice (SJL) and it was confirmed that two distinct prion strains had been identified. MRC1 was characterized by a short incubation time (110±3 days), a mono-glycosylated-dominant PrPSc type and a generalized diffuse pattern of PrP-immunoreactive deposits, while MRC2 displayed a much longer incubation time (155±1 days), a di-glycosylated-dominant PrPSc type and a distinct pattern of PrP-immunoreactive deposits and neuronal loss. These data indicate a crucial involvement of the host genome in modulating prion strain selection and propagation in mice. It is possible that multiple disease phenotypes may also be possible in BSE prion infection in humans and other animals.

Malgré des efforts répétés et soutenus lors des 30 dernières années, le nombre de modèles permettant l’étude en culture cellulaire de la multiplication des prions était, jusqu’à récemment, extrêmement restreint. Il s’agissait, pour l’essentiel, de quelques lignées cellulaires, ne permettant la multiplication que de rares souches expérimentales de prions. Pour tenter de pallier ces insuffisances, un projet a été initié en vue d’établir des modèles capables notamment de permettre la multiplication et l’étude de souches naturelles de prions. Quatre nouveaux modèles cellulaires ont été obtenus. S’ils sont tous permissifs à la multiplication du prion ovin, chacun d’entre eux présente des caractéristiques originales qui permettront une étude approfondie de divers aspects de la pathogenèse de ces maladies à l’échelon cellulaire. L’approche développée ici avec succès pourrait être appliquée à l’établissement de modèles permettant la multiplication de prions bovins ou humains. Des études sont menées actuellement à partir de ces modèles cellulaires, et portent sur les conséquences de l’infection sur l’activité neuronale, l’identification de cellules responsables de la multiplication de l’agent dans le système nerveux périphérique, l’interaction entre prion pathogène et cellule cible, l’analyse de la dérégulation de certains gènes de la glycosylation en cas d’infection, l’identification de molécules ayant une activité antiprions, et le rôle du polymorphisme de la PrP ovine dans réplication du prion pathogène., Although numerous attempts have been made duringthe last 30 years to generate cellular models of prioninfection, very few cell models were available untilrecently. A few cell lines allowed the multiplication ofa very small number of experimental prion strains. Aproject was initiated to compensate for the lack of acellular system permissive to the multiplication of naturalstrains of prions. Four models have been generated.They are all permissive to ovine prion multiplicationand each has distinct features that should help to studythe different aspects of prion pathogenesis. In addition,the strategy used to derive these models couldalso be used to generate cell models of human or bovineprion infection. The ongoing work includes studieson the effects of prion infection on neuron biology, onthe identification of permissive cells in the peripheralnervous system, on the interaction of prions with thetarget cells, on the deregulation of genes involved inglycosylation, on the identification of drugs with antiprionactivity and on the role of PrP polymorphisms inscrapie susceptibility.

During the past two decades, considerable efforts have been made to set up tissue culture models of genetic and infectious forms of TSEs and cellular cultures supporting TSE agent replication [1]. These models present, from both a fundamental and applied point of view, several advantages in comparison with in vivo models. They provide the ability to analyze at both the molecular and cellular levels, the biological properties of PrPC and PrPSc. They also permit to investigate the nature of the infectious agent and the factors governing its propagation and, importantly, they can be used to screen drugs with potential therapeutic value.

Most of the infectious diseases imply biological regulations controlled by several feedback loops or circuits. Kinetic logic, which is a method easily accessible to biologists or physicians, and which takes time and thresholds of activity into account, seems a convenient method for building simplified models related to this field. This implies usually qualitative predictions concerning the dynamics of such biological systems, leading to a movement back and forth between experimentation or observation and logical description. Here, we illustrate this simple modelling method in building elementary models concerning prion infection to demonstrate how to proceed. We also discuss and summarize how this method has been used for studying several viral diseases. As an example, we show how predictions related to the rhabdovirus cycle, were experimentally verified.

Prion diseases are fatal, infectious, neurodegenerative disorders, and there are no available therapeutic or prophylactic regimens. The potential of immune system components in combating peripheral prion infection has long been underestimated, but recent studies have suggested that such molecules could be effective. For example, promising results have been reported from a passive vaccination study in prion-infected mice. In addition, elegant transgenic mouse studies have shown the inhibitory effect on prion propagation of a soluble immunoglobulin G (IgG)-like dimeric prion protein. This type of molecule might represent a new class of anti-prion compounds.

For more than two decades it has been contended that prion infection does not elicit immune responses: transmissible spongiform encephalopathies do not go along with conspicuous inflammatory infiltrates, and antibodies to the prion protein are typically undetectable. Why is it, then, that prions accumulate in lymphoid organs, and that various states of immune deficiency prevent peripheral prion infection? This review revisits the current evidence of the involvement of the immune system in prion diseases, while attempting to trace the elaborate mechanisms by which peripherally administered prions invade the brain and ultimately cause damage. The investigation of these questions leads to unexpected detours, including the neurophysiology of lymphoid organs, and even the function of a prion protein homolog in male fertility.

In this paper, we propose the hypothesis that the long incubation period of prion infections is dependent upon a low rate of pathological prion formation and accumulation. Reduced pathological prion formation might be caused by the high content of β-sheets in the molecule. β-Sheet folding appears to proceed more slowly than folding of α-helices; the former are a major component of the prion secondary structure. This hypothesis strongly agrees with the data about folding of the artificial protein l-polylysine. This protein exists in two subforms: a rapidly folding α-helix-enriched form and a β-sheet-rich form having a very slow speed of secondary and tertiary structure formation. According to our hypothesis, the limiting factor for prion infection propagation is the speed of β-sheet folding in molecules of pathological prion but not the speed of migration of this protein through the host organism.

We present a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., mad cow disease) with concomitant prion protein misfolding and aggregation. Our studies lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self-averaging. We model "species barriers" to prion infection and assess a related treatment protocol.

Laurent (1996a, Médecine/sciences12, 774-785; 1996b, Biochem. J.318, 35-39; 1998, Bio-phys. Chem.72, 211-222) proposed a model for the dynamics of diseases of the central nervous system caused by prions. It is based on the protein-only hypothesis (Prusiner et al., 1981, Proc. Natl. Acad. Sci. U.S.A.78, 6675-6679), which assumes that infection can be spread by particular proteins (prions) that can exist in two forms that share the same sequence, but have a different structure. The normal form is harmless, while the infectious isoform of the prion protein catalyses a transconformation from the native isoform to itself within a specialized compartment of the brain cells. This paper systematically explores the model behavior with the aim of quantifying the fundamental parameters characterizing the dynamics of prion infection. To this end we use data from the literature to fix orders of magnitude for the rates of synthesis and degradation of the native form of prion protein and for the shape of the autocatalytic function. The dynamical behavior is classified with respect to two unknown parameters (bifurcation analysis): the rate of spontaneous transconformation and the rate of output of the infectious isoform from the specialized compartment. We thus find that the bistability properties evidenced by Laurent are confined to a certain range of parameters and that permanent oscillations of the two isoforms concentrations are possible. The bifurcation analysis allows us to estimate approximate ranges for the values of the two unknown parameters and consequently to derive incubation times and compare them with actual data for hamster. Also, our study predicts that the output rate of the infectious isoform is relatively insensitive to variations of model parameters.

Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt–Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPScthrough a posttranslational process during which it acquires a high β-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPScacts as a template upon which PrPCis refolded into a nascent PrPScmolecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrPSc. While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

Some human neurodegenerative diseases, such as Kuru, Creutzfeld-Jacob, Gerstmann-Streussler-Scheinker, as well as the animal ones (scrapie in sheeps, mad cow desease, etc.), are transmitted by prion, an infectious protein PrPSc. This protein is an oligomer form of the normal cellular neuropeptide PrPC. Both proteins are encoded by the same gene PrP, which is conserved at least among mammals. Mutations within the gene cause familial forms of the same prion diseases in men. In the latter case duplications of characteristic aminoacid repeats had been discovered in the N-terminal part of PrP protein. Deletion of PrP gene in mice confers resistance to prion infection in the animal. Overexpression of the same gene induces PrPSc and prion disease in mice (see a review by Wickner et al1).

It is suggested that the agent for transmissible spongiform encephalopathies is transferred from an original peripheral site of infection into the brain by recruited and selected circulating macrophages/monocytes. It is because of this selection that strains of disease appear to be different when infecting separate species, but retain characteristics when infecting a single species.

Accumulating lines of evidence indicate that the N-terminal domain of prion protein (PrP) is involved in prion susceptibility in mice. In this study, to investigate the role of the octapeptide repeat (OR) region alone in the N-terminal domain for the susceptibility and pathogenesis of prion disease, we intracerebrally inoculated RML scrapie prions into tg(PrPΔOR)/Prnp 0/0 mice, which express mouse PrP missing only the OR region on the PrP-null background. Incubation times of these mice were not extended. Protease-resistant PrPΔOR, or PrP ScΔOR, was easily detectable but lower in the brains of these mice, compared to that in control wild-type mice. Consistently, prion titers were slightly lower and astrogliosis was milder in their brains. However, in their spinal cords, PrP ScΔOR and prion titers were abundant and astrogliosis was as strong as in control wild-type mice. These results indicate that the role of the OR region in prion susceptibility and pathogenesis of the disease is limited. We also found that the PrP ScΔOR, including the pre-OR residues 23-50, was unusually protease-resistant, indicating that deletion of the OR region could cause structural changes to the pre-OR region upon prion infection, leading to formation of a protease-resistant structure for the pre-OR region., PLoS ONE, 7(8), e43540; 2012

To the Editor: Prusiner1 and Roos2 (May 17 issue) do not mention the spread of prions by contaminated surgical instruments. Since prions are not inactivated by the usual methods of sterilization, surgical procedures may account for some cases of sporadic Creutzfeldt–Jakob disease.3 Responding to this concern, the United Kingdom Department of Health has mandated that all tonsillectomy procedures be carried out with single-use instruments and has identified other procedures in which single-use instruments must be used. Instruments should not be reused after use in a patient with known or suspected Creutzfeldt–Jakob disease. Since it is unrealistic to expect that all . . .

THERAPIES FOR FIGHTING prion diseases are beginning to emerge, and one agent is already being used to treat people. Prions are infections proteins believed to cause mad cow disease, Creutzfeldt-Jakob disease (CJD) in humans, and related fatal conditions for which there currently are no treatments. Postdocs Carsten Korth and Barnaby C. H. May, professor of medicine and pharmacology Fred E. Cohen, and neurology and biochemistry professor Stanley B. Prusiner of the University of California, San Francisco, have rediscovered two approved tricyclic drugs—the antimalarial agent quinacrine and the antipsychotic chlorpromazine—and have confirmed that they inhibit prion infection in cells [ Proc. Natl. Acad. Sci. USA , 98,9836 (2001)]. Clinical trials in human CJD patients are planned for both drugs, individually and in combination, and quinacrine is already being administered to two patients on a compassionate-use basis, one of whom has reportedly improved markedly. Prusiner and coworkers identified the drugs inde...

The mechanisms implicated in prion infection and tissue distribution are not completely understood. In this study we investigated the levels of 263K prions in brain and spleen of Syrian hamsters few days after intra-peritoneal challenge. For this purpose we utilized the PMCA technology which permits to detect as little as few PrPSc molecules. Our results show that peripherally administered prions directly reach the brain, although at levels below the minimum necessary to produce disease. PrPSc remains in the brain several days after administration suggesting inefficient clearance or early replication. Understanding the fate of the infectious agent after administration and its uptake in different organs and fluids may provide useful information to develop strategies to minimize further spreading of prion diseases.

Summary Prion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrP C , into a protease-resistant form, PrP Sc . Here, we show that mutation-induced thermodynamic stabilization of the folded, α-helical domain of PrP C has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrP C →PrP Sc conformational transition, and they suggest an approach to the treatment of prion diseases.

A theory has been developed that could explain prion infection. Prions could be molecular chaperones that are required for their own assembly. The theory has been deduced from an analysis of protein folding and consequences explored by computer simulations. Thermo-kinetic analysis of protein folding shows that a misfolded chaperone gives rise to new misfolded chaperones. Consequently such a protein could behave as a new kind of informative molecule and replicate misfolding according to a process similar to infection. A quantitative model has been derived from this hypothesis that displays the characteristics of prion infections. This hypothesis satisfactorily explains the three manifestations infection, familial and sporadic — that are the characteristics features of all prion diseases.

Transmissible spongiform encephalopathies or prion diseases are fatal neurodegenerative pathologies characterized by the autocatalytic misfolding and polymerization of a cellular glycoprotein (cellular prion protein [PrP(C)]) that accumulates in the CNS and leads to neurodegeneration. The detailed mechanics of PrP(C) conversion to its pathological isoform (PrP(TSE)) are unclear but one or more exogenous factors are likely involved in the process of PrP misfolding. In the last 20 years, proteomic investigations have identified several endogenous proteins that interact with PrP(C), PrP(TSE) or both, which are possibly involved in the prion pathogenetic process. However, current approaches have not yet produced convincing conclusions on the biological value of such PrP interactors. Future advancements in the comprehension of the molecular pathogenesis of prion diseases, in experimental techniques and in data analysis procedures, together with a boost in more productive international collaborations, are therefore needed to improve the understanding on the role of PrP interactors. Finally, the advancement of 'omics' techniques in prion diseases will contribute to the development of novel diagnostic tests and effective drugs.