Adriano Aguzzi

..This overview summarizes some current hypotheses about the nature of the infectious agent and about the pathogenesis of the damage of the central nervous system...

..This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection...

..There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa...

..These results indicate that PrPc exerts a neuroprotective role against KA-induced neurotoxicity, probably by regulating the expression of KA receptor subunits...

..Although research in the past has accumulated knowledge on prion progression from the periphery to the brain, we are far from understanding the molecular mechanisms of neuronal prion transport...

..It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component...

..Here we review these developments and summarize those open questions that we currently deem most interesting in prion biology: how do prions damage their hosts, and how do hosts attempt to neutralize invading prions?..

..Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD...

..In 2001, the observed annual mortality from Creutzfeldt-Jakob disease (CJD) in Switzerland increased from less than 1.5 to 2.6 per million inhabitants. An underlying cause could not be identified...

..Here, we discuss the molecular mechanisms leading to neurodegeneration, the role of the immune system in prion pathogenesis, and the existence of prion strains that appear to have different tropisms and biochemical characteristics...

..Chakrabarti and Hegde (2009) now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology...

....

..Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions...

..This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields...

..Here we review the salient traits of those diseases ascribed to improper behavior of the prion protein and highlight how the physiological functions of PrP(C) may help explain the toxic phenotypes observed in prion disease...

....

....

..Here we review the current state of FDC science with specific reference to a study in this issue of the European Journal of Immunology and its efforts in discovering new FDC markers...

..Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics...

..The existence of such strains poses a fascinating challenge to prion research...

..Here we focus on the unresolved issues pertaining to prion pathogenesis, particularly on the role played by the immune system...

..Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8(-/-) mice. Hence, FDCs facilitate TBMphi-mediated corpse removal, and their malfunction may be involved in autoimmunity...

..We conclude that, surprisingly, there are no universal transcriptional changes induced by prion infection of neural cells in vitro...

..These results identify white-matter damage as an extraneuronal PrP-associated pathology and suggest a previously unrecognized role of PrP(C) in myelin maintenance...

..Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC...

..Hence, in contrast to previous reports, microglia are not competent for efficient prion transport and replication in vivo...

..By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission...

..Hence, granulomas can act as clinically silent reservoirs of prion infectivity. Furthermore, lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs...

..These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance...

....

....

....

..This suggests that the extensive microglial activation accompanying prion diseases represents an efficacious defensive reaction...

..Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease...

..The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation...

..Hence oligodendrocytes do not support cell-autonomous prion replication, establishment of subclinical disease, and neural spread of prions. Prion resistance sets oligodendrocytes aside from both neurons and astrocytes...

....

..This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease...

..Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrP(Sc) deposits...

..LCPs may help to detect structural differences among discrete protein aggregates and to link protein conformational features with disease phenotypes...

..ii) Expression of LTbeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread...

....

..Alternatively, Dpl and PrP(C) may exert distinct functions despite having partly overlapping expression profiles...

..Selected PrP(C) interactors were validated using independent methods. Several of these proteins appear to exert functions in axomyelinic maintenance...

..Therefore, moderate intestinal inflammation at the time of prion exposure may constitute one of the elusive risk factors underlying the development of TSE...

..Because both PrP(C) and CD21/35 are highly expressed on follicular dendritic cells, CD21/35 appears to be involved in targeting prions to follicular dendritic cells and expediting neuroinvasion following peripheral exposure to prions...

..Macrophage subsets are plausible candidates for lymphoreticular prion pathogenesis and neuroinvasion in the absence of FDCs, and may represent a novel target for postexposure prophylaxis...

..Hence, the set of genes presented in this study includes markers emanating from LTbetaR signaling and transcripts relevant to GC and FDC function...

..These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP(C), whose effector domain encompasses residues 94-134...

....

..The unique properties of PrP-Fc(2) suggest that soluble PrP derivatives may represent a new class of prion replication antagonists...

....

..M cells are a plausible candidate for the mucosal portal of prion infection...

....

..These results suggest that alpha-cleavage is executed by an alpha-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrP(C)...

..The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo...

..Although susceptibility to prion infection following oral challenge correlates with the number of PPs, it is remarkably independent of the number of PP-associated lymphocytes...

..Thus, urine may provide a vector for horizontal prion transmission, and inflammation of excretory organs may influence prion spread...

..This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories...

..Its circumvention might represent an important step toward the development of effective anti-prion immunotherapy...

..Hence, prions may enter lymph nodes by HEVs and accumulate or replicate in the absence of mature FDCs...

..These factors may account for their resistance to infection. Alternatively, prion resistance may be related to the specific sequence of canine Prnp, as suggested by the lack of documented prion diseases in dogs...

..In this article, we review the state of knowledge on the routes of neuroinvasion used by the infectious agent in order to gain access to the central nervous system upon entry into extracerebral sites...

..Also, incubation times and clinical course of prion disease, as well as brain infectivity titres at terminal stage, were unaffected. These data rule out neprilysin as a major modulator of PrPSc accumulation and prion pathogenesis...

....

..We report that ablation or overexpression of PrP(C) had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrP(C) as a mediator of Abeta toxicity...

..These results suggest that somatic gene transfer of prion antagonists may be effective for postexposure prophylaxis of prion diseases...

..The simple yeast organism has served as a valuable model for understanding aspects of prion biology, such as prion fibril assembly...

..These findings indicate that the salient strain-specific properties of CWD are encoded by agent-intrinsic components rather than by host factors...

..The present review article discusses current concepts and controversies surrounding the basic biological features of prions...

....

..The two decades since Stanley Prusiner's formulation of the protein-only hypothesis have witnessed spectacular advances, and yet some of the most basic questions in prion science have remained unanswered...

..The coincidence of tau and prion pathology resembled Gerstmann-Sträussler-Scheinker syndrome. These findings identify tau pathology as a possible end stretch of prion-induced neurodegeneration...

..A recently published study demonstrated the presence of pathological prion protein in sympathetic ganglia of patients suffering from variant Creutzfeldt-Jakob disease, suggesting that these mechanisms might apply to humans...

..The difficulties involved in eliciting development of such anti-native PrPC immune responses may be partly intrinsic to B cells and, in addition, may reside in peripheral T helper tolerance...

..TLR signalling therefore does not have any major role in prion pathogenesis, and the protective effect of TLR stimulation is unlikely to result from direct interactions with prions...

....

..This article reviews the pathophysiology of prion diseases in mouse models and discusses their relevance to immunotherapeutic and immunoprophylactic antiprion strategies...

..We conclude that PrP(C) in vivo does not discernibly contribute to total SOD activity and does not possess an intrinsic dismutase activity...

..These results indicate that DRMs are essential for proper trafficking and distribution of PrP(C) at late stages of neuronal differentiation and that its function, at least in hippocampus, is restricted to the axonal domain...

..Although we are only beginning to understand its function, the discovery of Dpl has already provided some answers to long-standing questions and is transforming our understanding of prion biology...

..These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation...

....

..Doppel and truncated PrP probably cause Purkinje cell degeneration by the same mechanism...

....

..This appears to be due to an alteration of the follicular dendritic cell (FDC) network within the lymphoid tissue, thereby reducing the distance between FDCs and adjacent nerve fibers that mediate prion neuroinvasion...

..These results indicate that 14-3-3gamma is unlikely to play a causal role in CJD and related diseases...

..Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease...

....

..Finally, there are hardly any therapeutic strategies. However, not all is gloomy, and many recent developments have advanced our basic understanding of prion diseases...

..Furthermore, the infectious agent may be less pathogenic towards ENS neurons than it is towards central nervous system neurons...

..Taken together, these data indicate a link between intracellular events induced by exposure to extracellular fibrillar peptide or PrP(res), and APP processing and implicate Dab1 in this link...

..Furthermore, a pathogenic PrP missense mutation within the HD leads to aberrant apical sorting of PrP as well...