1. Preface and Introduction

Takashi Onodera and Akikazu Sakud

Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in cervids. A key event in prion diseases is the conversion of the cellular, host-encoded prion protein (PrP^C) to its abnormal isoform (PrP^Sc) predominantly in the central nervous system of the infected host (Aguzzi et al. 2004).The diseases are transmissible under some circumstances, but unlike other transmissible disorders, prion diseases can also be caused by mutations in the host gene. The mechanism of prion spread among sheep and goats that develop natural scrapie is unknown. CWD, transmissible mink encephalopathy (TME), BSE, feline spongiform encephalopathy (FSE), and exotic ungulate encephalopathy (EUE) are all thought to occur after the consumption of prion-infected material. Most cases of human prion disease occur from unknown reasons, and >20 mutation in the prion gene may lead to inherited prion disease. In other instances, prion diseases are contracted by exposure to prion infectivity. This raises the question of how a mere protein aggregate can trespass mucosal barriers, circumvent innate and adoptive immunity, and travel across the blood-brain barrier to eventually provoke brain disease. To start the chapters of this book we will introduce a few topics in current prion studies.

2. Prion Protein and the Family Members, Doppel and Shadoo

Akikazu Sakudo

Prion diseases are devastating neurodegenerative disorders caused by infectious proteinaceous agents known as prions. Prion protein (PrP) gene (Prnp)-deficient mice do not infect with prion agent, indicating essential role of PrP for prion diseases. An abnormal isoform of prion protein (PrP), known as PrP^Sc, which is converted from cellular PrP (PrP^C), is thought to constitute the prion agent. Recently, proteins homologous to PrP have been found, suggesting the existence of other PrP family members, which so far include PrP, Doppel (Dpl) and Shadoo (Sho). In this chapter, the author introduces recent research on the physiological function of PrP and PrP-related proteins together with our own studies.

3. Function of Cellular Prion Protein

Takashi Onodera, Katsuaki Sugiura, Shigeru Matsuda and Akikazu Sakudo

Although much is known about the effect of PrP^Sc in prion diseases, the normal function of PrP^C is poorly understood. PrP^C may act as an antiapoptotic agent by blocking some of the internal environmental factors that initiate apoptosis. PrP-knockout methods provide powerful hints on the neuroprotective function of PrP^C. Using PrP^C-knockout cell lines, the inhibition of apoptosis through STI1 is mediated by PrP^C-dependent SOD activation. Recently several reports show that PrP^C participate in trans-membrane signaling process associated with hematopoietic stem cell replication and neuronal differentiation. Besides PrP-knockout exhibited wide spread alterations of oscillatory activity in the olfactory bulb as well as altered paired-pulse plasticity at the dendrodendric synapse. Both the behavioral and electro-physiological phenotypes could be rescued by neuronal PrP^C expression. Neuprotein Shadoo (Sho), similarly to PrP^C, can prevent neuronal cell death induced by the expression of PrP△HD mutants, an artificial PrP mutant devoid of internal hydrophobic domain. Sho can efficiently protect cells against exito-toxin-induced cell death by glutamates. Sho and PrP seem to be dependent on similar domains, in particular N-terminal (N) and their internal hydrophobic domain. Sho△N and Sho△HD displayed a reduced stress-protective activity but are complex glycosylated and attached to outer leaflet of the plasma membrane via GPI anchor indicating that impaired activity is not due to incorrect cellular trafficking. In Shadoo over-expressed mice showed large amyloid plaques not seen in wild-type mice. However Shadoo is not a major modulator of PrP^Sc accumulation and scrapie pathogenesis. Sho and PrP share a stress-protective activity. The ability to adopt a toxic conformation of PrP^Sc seems to be specific for PrP.

4. Effect of Microglial Inflammation in Prion Disease

Yasuhisa Ano, Akikazu Sakudo and Takashi Onodera

Prion diseases are a group of transmissible fatal neurodegenerative disorders. Neuropathological features of prion diseases include neuronal vacuolation, neuronal loss, astrogliosis, and accumulation of activated microglial cells in affected brain areas. Recent studies have indicated that microglia may play a role in the pathogenesis of prion diseases. Chemokine receptor (CXCR3) expressed in microglia and microglial inflammasome activated by prion infection is important in the etiology of CNS pathologies. pathologies. The functions of microglia in this disease are discussed in this review.

5. Molecular Mechanisms of Prion Diseases

Hermann C. Altmeppen, Berta Puig, Susanne Krasemann, Clemens Falker, Frank Dohler and Markus Glatzel

Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative conditions occurring in humans and animals that may be transmitted. Experimental data and neuropathological examinations show that prions (here defined as the agent responsible for transmissible spongiform encephalopathies) consist of a self-propagating isoform of the cellular prion protein. Nucleic acids are not required for propagation of prions. In the last years a number of questions regarding the mechanism of prion propagation and neurotoxicity as well as the spread of prions to and within the brain have been answered, yet essential pieces of information regarding the execution of cell death and cell-to-cell spread of prions remain to be elucidated.

6. Inactivation of Prion and Endotoxins

Hideharu Shintani and Gerald McDonnell

Several inactivation procedures to prion and endotoxins are reported so far. Most of these methods are not applicable to re-usable medical devices due to failure of achievement of material and functional compatibility. Gas plasma inactivation procedure for prion and endotoxin was studied and attain both sterility assurance level (SAL) of 10^-6 and material and functional compatibility in ease.

7. Clinical Aspects of Human Prion Diseases

Richard Knight

Human prion disease is divided into three broad classes: Idiopathic, Genetic and Acquired. There are significant differences in clinical presentation both between and within these three groups, but all are progressive, fatal brain diseases with dementia, cerebellar ataxia and involuntary movements being particularly prominent features. Absolutely definite diagnosis requires neuropathological analysis of brain tissue but there are established clinical diagnostic criteria and a variety of supportive investigations including abnormalities in the EEG, cerebral MRI and CSF protein analysis. For variant CJD, tonsil biopsy is an additional test and, in genetic prion disease, blood testing for pathogenic PRNP mutations is possible.

8. Immunological Strategies for the Prevention and Treatment of Prion Diseases

Keiji Uchiyama and Suehiro Sakaguchi

Prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in animals, are a group of incurable neurodegenerative disorders caused by proteinaceous infectious agents, the so-called prions. No preventative vaccines and therapeutics of prion diseases have been developed. Recent lines of evidence suggest that antibodies against prion protein might be beneficial for both preventing and treating prion disease. In this chapter, we first discuss the possibility that there might be many individuals who are latently infected with vCJD prions in human populations, and then introduce the so far reported immunological approaches for development of prion vaccines and immunotherapy against prion disease, including our recent work.

9. Bovine Spongiform Encephalopathy and Scrapie

Takashi Yokoyama

Bovine spongiform encephalopathy (BSE) emerged more than 2 decades ago, and until today, over 190,000 heads of cattle have been diagnosed. An effective feed ban program has diminished the outbreak worldwide; however, different phenotypes of BSE (atypical BSEs) have emerged. Additionally, a different phenotype of scrapie (atypical scrapie) was reported in 1998. The prevalence of these diseases is low and suggests the possibility that they are spontaneous forms of prion diseases. The decline in BSE outbreaks has led to discussion for the withdrawal of some control programs. However, despite their unknown origin, the transmissibility of these atypical animal prion diseases has been demonstrated. Pre-emptive measures are necessary in order to prevent future outbreaks of atypical prion diseases in animals.

10. Chronic Wasting Disease and Other Animal Prion Diseases

Akikazu Sakudo

Chronic wasting disease (CWD) is one of the prion diseases showing clinical symptoms such as progressive weight loss, abnormal behaviour and excessive salivation. Incidents have been reported in North America and Korea. Efficient transmission by horizontal infection possibly occurs via saliva or faeces. Infectivity in the skeletal muscle of infected deer has been observed, suggesting meat could be a potential source of infection. However, at the moment, CWD transmission to humans is thought to be very unlikely. In this chapter, we also introduce representatives of other animal prion diseases, such as transmissible mink encephalopathy (TME) and feline spongiform encephalopathy (FSE). Recently, possible transmission of CWD to fishes has also been reported.

11. Future Prospect

Takashi Onodera and Katsuaki Sugiura

Results in Netherlands show that classic scrapie control can be obtained at the national scale without a loss of genetic polymorphism from any of sheep breed. No classical scrapie strain thus far has escaped ARR-associated resistance. Ongoing studies show that atypical scrapie strain also was controlled by ARR-associated resistance. In line with this expectation, the breeding program proved successful in Dutch flock in 2010. When considering the rapid outbreak control as observed in Netherland study, the use of resistant rams seems sufficient and can be recommended as a control strategy in scrapie-affected countries. The origin of atypical BSE cases is currently unknown. As with classical BSE, exposure of these animals to feed contaminated with low titers of TSE agent cannot be excluded, although other origins for these TSE forms cannot be discarded. In particular, the unusually old ages of all H-BSE and L-BSE identified cases and their apparent low-prevalence in the population could suggest that these atypical BSE forms are arising spontaneously. PMCA needs to be highly standardized and robust in terms of a consistent and objectively quantifiable PrPres amplification if to be used for quantification of the proteinaceous seeding activity of prions. There is a direct quantitative correspondence between the seeding and infectious activities of 263K scrapie prions measured by RT-QuIC and bioassay. The methodological, conceptual and practical results described in the report of 263K scrapie prions should be validated for the most human TSE agents. Although scrapie has been known for decades, relatively little attention has been paid to it as a natural disease of sheep and goats mainly because the economical impact has been relatively small compared to other diseases in sheep. The occurrence of bovine spongiform encephalopathy (BSE) provide a new impetus to research into the transmissible spongiform encephalopathies (TSE). Not only was the economical impact of BSE much greater than that of scrapie, the link with variant Creutzfeldt-Jakob disease (vCJD) in humans also gave rise to serious concerns regarding food safety.