Prions: Current Progress in Advanced Research (Second Edition) | Book
Caister Academic Press
and Takashi Onodera2
1School of Health Sciences, University of the Ryukyus, Okinawa, Japan. 2Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan.
vi + 154
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Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurological diseases that include, for example, Creutzfeldt-Jakob Disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Since the publication of the first edition of this book in 2013 significant progress has been made in advanced prion research creating a need for this timely revised and updated edition.
The book opens with an introductory chapter that provides an overview. This is followed by four chapters (chapters 2-5) dealing with fundamental aspects of prion biology, including functions of the cellular isoform of prion protein (PrPC) and molecular mechanisms of prion diseases. The next two chapters (chapters 6-7) focus on clinical aspects of human prion diseases and current approaches for effective inactivation methods. The last part of the book (chapters 8-9) summarizes animal prion diseases, including BSE, scrapie and chronic wasting disease (CWD). In the final chapter, Professor Onodera discusses the likely future direction of research.
This book is essential reading for everyone working with prions from the PhD student to the experienced scientist, in academia, the pharmaceutical or biotechnology industries and for those working in clinical environments.
Table of contents
1. Introduction to Current Progress in Advanced Research on Prions
Takashi Onodera and Akikazu Sakudo
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, camel spongiform encephalopathy (CSE) in camels (Babelhadj et al. 2018) and chronic wasting disease (CWD) in cervids. A key event in prion diseases is the conversion of the cellular, host-encoded prion protein (PrPC) to its abnormal isoform (PrPSc) predominantly in the central nervous system of the infected host (Aguzzi et al. 2004). These 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 mutations in the prion protein (PrP) gene may lead to inherited prion disease. In other instances, prion diseases are contracted by exposure to prion infectivity. These considerations raise the question of how a mere protein aggregate can bypass mucosal barriers, circumvent innate and adoptive immunity, and traverse the blood-brain barrier to give rise to brain disease. Here, we will briefly introduce a few topics in current prion studies.
2. Function of Prion Protein and the Family Member, Shadoo
Takashi Onodera, Takuya Nishimura, Katsuaki Sugiura and Akikazu Sakudo
Lowering cellular prion protein (PrPC) levels in the brain is predicted to be a powerful therapeutic strategy for the prion disease. PrPC may act as an antiapoptotic agent by blocking some of the internal environmental factors that initiate apoptosis. Prion protein (PrP)-knockout methods provide powerful indications on the neuroprotective function of PrPC. Using PrPC-knockout cell lines, the inhibition of apoptosis through stress inducible protein1 (STI1) is mediated by PrPC-dependent superoxide dismutase (SOD) activation. 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 behavioural and electro-physiological phenotypes could be rescued by neuronal PrPC expression. Neuprotein Shadoo (Sho), similarly to PrPC, 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 the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI) anchor indicating that impaired activity is not due to incorrect cellular trafficking. In Sho, over-expressed mice showed large amyloid plaques not seen in wild-type mice. However, Shadoo is not a major modulator of abnormal prion protein (PrPSc) accumulation. Sho and PrP share a stress-protective activity. The ability to adopt a toxic conformation of PrPSc seems to be specific for PrP.
3. 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 neuroinflammation featuring the infiltration of activated microglia in affected brain areas as well as the accumulation of an abnormal isoform of the cellular prion protein and neuronal loss. Recent studies have elucidated that inflammation in the brain induced by microglia plays an important role in the pathogenesis of neurodegenerative disorders including prion disease. Thus, the regulation of neuroinflammation is key in terms of therapeutic and preventative approaches. The functions of neuroinflammation and microglia in this disease are discussed in this chapter.
4. Prion Propagation, Its Neurotoxicity, and Protein Trafficking
Suehiro Sakaguchi and Keiji Uchiyama
Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform of prion protein, PrPSc, which leads to its accumulation or propagation, is a key pathogenic event in prion diseases which are a group of fatal neurodegenerative disorders. We recently reported that the VPS10P sorting receptor, sortilin, negatively regulates PrPSc accumulation in prion-infected neurons, by trafficking PrPC and PrPSc to lysosomes for degradation, and that PrPSc conversely stimulates lysosomal degradation of sortilin, thereby disrupting the sortilin-mediated degradation of PrPC and PrPSc. These results suggest a positive feedback amplification mechanism for PrPSc accumulation in prion-infected neurons. We also showed that prions could selectively impair post-Golgi vesicular trafficking well before mice became sick after infection, suggesting that the post-Golgi vesicular trafficking impairment could be an early pathogenic event in prion diseases. Here, we will discuss our current findings in detail.
5. Molecular Mechanisms of Prion Diseases
Hermann C. Altmeppen, Berta Puig, Susanne Krasemann and Markus Glatzel
Prion diseases or transmissible spongiform encephalopathies (TSE) are transmissible, fatal neurodegenerative conditions occurring in humans and animals. Experimental data and neuropathological examination show that prions (here defined as the agent responsible for TSEs) consist of a self-propagating isoform (PrPSc) of the cellular prion protein (PrPC). 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. Clinical Aspects of Human Prion Diseases
Richard Knight and Graeme Mackenzie
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 that have included 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. Recent developments, based on prion protein amplification and detection, have resulted in a number of sensitive and more specific diagnostic tests.
7. Inactivation Methods for Prions
Incidences of iatrogenic Creutzfeldt-Jakob disease (iCJD) are caused by transplantation of prion-contaminated hormones, cornea and dura mater as well as contact with prion-contaminated medical devices, such as stereotactic electrodes, used in neurosurgery. Because prions are highly resistant and difficult to inactivate, prion contamination is a severe risk when medical instruments are reused after surgical procedures involving suspicious and confirmed cases of patients with prion diseases. Therefore, when high-risk procedures such as cerebral surgery, craniotomy surgery, orthopaedic spinal surgery and ophthalmic surgery are performed for high-risk patients or individuals with prion diseases, it is necessary to appropriately treat the medical devices using scientifically proven prion inactivation methods. In this chapter, we introduce fundamental aspects of prion inactivation methods, looking specifically at the practical issues involved in their implementation.
8. Bovine Spongiform Encephalopathy and Scrapie
Takashi Yokoyama and Yoshifumi Iwamaru
Bovine spongiform encephalopathy (BSE) emerged more than three decades ago, and over 190,000 head of cattle have been diagnosed. An effective feed-ban programme has diminished the outbreak worldwide. Although the decline in BSE outbreaks has led to discussions for the withdrawal of some control programmes, different phenotypes of BSE (atypical BSEs) have emerged. Additionally, a different phenotype of scrapie (atypical scrapie) was reported in 1998. The prevalence of these atypical diseases is low and suggests the possibility that they are spontaneous forms of prion diseases. Despite their unknown origin, the transmissibility of these atypical animal prion diseases has been demonstrated.
9. Chronic Wasting Disease: Current Assessment of Transmissibility
Chronic wasting disease (CWD) is a prion disease of cervids characterized by clinical symptoms of progressive weight loss, abnormal behaviour and excessive salivation. Incidents have been reported in North America and Korea as well as in Europe. Current knowledge, based on in vitro and in vivo experiments, suggests direct CWD transmission to humans is unlikely. Nonetheless, humans may consume CWD-infected materials, which presents a potential risk. Studies indicate that transmission by horizontal infection of cervids probably occurs via saliva, faeces, and urine as well as from environmental reservoirs of prions found in soil and water. In addition, infectivity in the skeletal muscle of infected deer has been observed. These findings suggest that direct contact with infected animals and indirect contact with prion-contaminated materials are potential sources of infection. However, recent studies on the detection of pregnancy-related prion infectivity imply the potential transmission of CWD from mother to offspring. In this chapter, fundamental aspects of CWD are reviewed.
10. Future Perspectives in Prion Research
Takashi Onodera, Takuya Nishimura and Katsuaki Sugiura
Classic scrapie control can be obtained nationally without loss of genetic polymorphism from any sheep breeds according to recent results from the Netherlands. No classical scrapie strain thus far has escaped ARR-associated resistance. Ongoing studies show that an atypical scrapie strain is also controlled by ARR-associated resistance. In line with these findings, the breeding programme proved successful in a Dutch flock in 2010. When considering rapid outbreak control, as observed in the Netherlands study, the use of resistant rams seems sufficient and can be recommended as a control strategy in scrapie-affected countries. Protein misfolding cyclic amplification (PMCA) needs to be highly standardized and robust in terms of a consistent and objectively quantifiable PrPres amplification if it is 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 on 263K scrapie prions should be validated for most human transmissible spongiform encephalopathies (TSE) agents. It seems likely that PrPC participates in the pathogenesis of Alzheimer's disease (AD) by acting as a cellular receptor for oligomeric Aβ aggregates. Ablation of PrPC expression or reducing PrPC levels in the brain could be very important therapeutic strategies for CJD and AD. However, chronic treatment with PrPC-lowering drugs may reveal unexpected consequences in the brain. An extensive understanding of the role of PrPC within the brain, especially in humans, is urgently needed. Canadian scientists have succeeded in transmitting chronic wasting disease (CWD) orally in primates. Specifically, 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer or elk via intracerebral, oral, and skin exposure routes. Challenged intracranially with steel wire, or orally, primates were sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. All animals had variable signs of prion neuropathology in their spinal cords and brains. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia, and/or tremor. In four animals, wasting was observed; two of those had confirmed diabetes. CWD contamination in the environment is increasingly important in public health and wildlife. Although scrapie has been known for decades, it has received relatively little attention as a natural disease of sheep and goats mainly because its economic impact has been relatively small compared to other sheep diseases. The occurrence of bovine spongiform encephalopathy (BSE) provides a new impetus to research into the transmissible spongiform encephalopathies (TSE). Not only is the economic impact of BSE much greater than that of scrapie, but the link with variant Creutzfeldt-Jakob disease (vCJD) in humans also gave rise to serious concerns regarding food safety.
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(EAN: 9781910190951 9781910190968 Subjects: [medical microbiology] [microbiology] [virology] )