Prions and Diseases

Description:

Transmissible spongiform encephalopathies (TSE), known as prion diseases, have been recognized for nearly 300 years in animals and almost 100 years in humans. Modern studies, including the protein-misfolding cyclic amplification (PMCA), have greatly advanced our understanding of the pathogenesis of prion diseases and facilitated the identification of new prion diseases in animals and humans. In the second edition of Prions and Diseases, more than 60 leading researchers and clinicians worldwide provide an up-to-date discussion of these unique infectious pathogens and their associated diseases. The book provides up-to-date knowledge about the etiology, pathogenesis, classification, histopathological, and clinical aspects of the full range of animal and human prion diseases. As a result, the book contains by far the most authoritative views about the past, present, and future of prions and prion diseases. The new second edition covers such important emerging topics such as inherited human prion disease, stem-cell models in prion research, human prion disease surveillance, and gene therapy strategies.

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Preface

Almost 2 years ago, Mr. William Lamsback, editor from Springer, reached out to us about the possibility to work on a second edition of our book Prions and Diseases, whose first edition was published by Springer in 2013. We were told that the printed book sold well and had nearly 20,000 downloads online. Indeed, studies on prions and prion diseases have been popular since 2008 according to PubMed, and there is a strong demand for top experts in the field to report and discuss these new developments and advances.

Prions apparently have become the prototype of other misfolded proteins associated with more common neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Many principles and technologies developed originally from the investigation of prions and prion diseases have been widely applied to prion-like neurodegenerative diseases, such as cell-to-cell transmission, animal transmission studies, protein misfolding cyclic amplification (PMCA), and real-time quakinginduced conversion (RT-QuIC) assays. Because of these similarities, Stanley Prusiner, the Nobel laureate who discovered scrapie pathogens and coined term “prion” in 1982, redefined prions as “proteins that acquire alternative conformations that become self-propagating” in 2013: a characterization that underlines the applicability of the prion concept to all conformational degenerative diseases. As a result, more researchers and clinicians are becoming interested in the past and current prion research.

The first edition updated human and animal prion diseases from basic science to clinical diagnosis and possible treatments. The second edition, besides preserving the strengths of our first edition, adds major changes. First, the two volumes are combined into a single one. Second, the 37 chapters are grouped into 10 sections including history, general aspects of prions, conversion and strain of prions, environment and transmission of prions, modeling of prions, human prion disease and other pathogenies, animal prion diseases, yeast prions, diagnosis and human prion surveillance, and treatment. Third, new topics have been added including stem cell models, genetic prion diseases, new human prion diseases, skin biomarkers, protective role of cellular prion protein in tissue ischemic reperfusion injury, human prion disease surveillance, and gene therapy.

To date, two Nobel prizes (actually, maybe two and a half, if the Nobel prize in Chemistry to Kurt Wütrick, who worked extensively on the prion protein, is considered) have been awarded for research on prions. Given that many unsolved issues remain, it is likely that additional Nobel prizes will be awarded for new discoveries related to prions. Hopefully, this book will be useful to our future Nobel laureates.

Table of contents :

Preface
Contents
Part I: History
Chapter 1: Transmissible Spongiform Encephalopathy: From Its Beginnings to Daniel Carleton Gajdusek
1.1 In the Beginning …
1.2 Working Out the Biology (in Sheep)
1.3 The Mouse That Roared
1.4 The Nature of the Beast
1.5 The Transition from Biology to Molecular Biology
1.6 The Discovery of Kuru
1.7 The Kuru–CJD–Scrapie Triangle
1.8 Experimental Transmission of Kuru
1.9 The Expanding Horizon of Transmissible Spongiform Encephalopathy
1.10 Clinical and Epidemiological Precisions
1.11 Therapeutic Essays
1.12 The End of an Era
References
Part II: General Aspects of Prions
Chapter 2: The Rich Chemistry of the Copper and Zinc Sites in PrPC
2.1 Introduction
2.2 Brief History
2.3 Features of Cu2+ and Zn2+ Coordination in PrP
2.4 A Role for Altered Copper Coordination in Octarepeat Expansion Disease
2.5 Electrochemical Properties of the PrP Copper Sites
2.6 Copper Regulation of PrPC Proteolytic Cleavage
References
Chapter 3: PrP Prion Structures
3.1 Introduction
3.2 Development of Initial Parallel In-Register and 4-Rung β-Solenoid Models for PrPSc Fibrils
3.3 Cryo-EM of Synthetic PrP Fibrils
3.4 Near-Atomic Cryo-EM Structures of Infectious Tissue-Derived Prions
3.5 PrPC to PrPSc Conversion
3.6 Impacts of Glycans and GPI Anchors
3.7 Structure-Based Modeling of Transmission Barriers
3.8 Conclusions
References
Chapter 4: Insoluble Cellular Prion Protein and Other Neurodegeneration-Related Protein Aggregates in the Brain of Asymptomatic Individuals
4.1 Introduction
4.2 Prion Protein Is Characterized by the Presence of an Intrinsically Chameleon-Like Conformation
4.3 Insoluble Cellular Prion Protein Aggregates Are Present in Mammalian Brains Without Prion-Infection
4.4 Spontaneous Formation of the Insoluble Cellular Prion Protein Has Been Modelled with Cultured Cells and May Result from PrP Cytosolic Accumulation
4.5 Physiology and Pathophysiology of Insoluble PrPC Aggregates
4.5.1 Long-Term Memory Storage
4.5.2 Prion Disease
4.5.3 Alzheimer’s Disease
4.6 Insoluble Aβ, Tau, and α-Synuclein Aggregates in the Brain of Asymptomatic Individuals
4.7 Conclusions
References
Part III: Conversion and Strain of Prions
Chapter 5: Prion Conversion and Deformed Templating
5.1 Introduction
5.2 Switching Between Alternative Folding Patterns Within Individual Amyloid Fibrils
5.3 Generating Transmissible Prion Diseases De Novo
5.4 Experimental Evidence Supporting the Mechanism of Deformed Templating
5.5 Deformed Templating In Vivo
5.6 Deformed Templating In Vitro
5.7 Prion Strain Mutation and Evolution via Deformed Templating
5.8 Role of Posttranslational Modifications in Driving Deformed Templating
5.9 Deformed Templating as a Mechanism of a Cross-Talk Between Amyloidogenic Proteins
References
Chapter 6: Prion Strain Interference
6.1 Introduction
6.2 Parameters Governing Prion Strain Interference
6.2.1 Overview
6.2.2 The Interval Between Prion Strains Inoculation Influences Interference
6.2.3 The Relative Titer of the Blocking and Superinfecting Strains Can Influence Interference
6.2.4 Blocking Strain Replication Is Required for Strain Interference
6.2.5 Infection of Common Neuroanatomical Pathways Is Required for Interference
6.3 Prion Strain Interference and the Replication Site Hypothesis
6.3.1 The Replication Site Hypothesis
6.3.2 The Role of PrPC in Prion Strain Interference
6.3.3 Prion Strain Interactions and Interconversion
6.4 Prion “Vaccination” and Strain Interference
References
Chapter 7: Molecular Mechanisms Encoding Strains of Prions and Prion-Like Misfolded Proteins
7.1 Prion Diversity
7.2 Distinct Phenotypes of Prion Strains in Bioassay
7.3 Prion Species
7.4 Cell Tropism of Prion Strains
7.5 Conformational Mechanism of Prion Strain Propagation
7.6 Molecular Attributes of Human Prion Strains
7.7 Mechanism of Formation, Replication, and Evolution of Human Prions
7.8 Expanding the Prion Strain Paradigm to Other Age-Related Neurodegenerative Diseases Caused by Protein Misfolding
7.9 Outlook
References
Chapter 8: Cofactor Involvement in Prion Propagation
8.1 The “Protein-Only” Hypothesis
8.2 Components of Purified Native Prions
8.3 Prion Replication in Cell-Free Conditions
8.4 Formation of Infectious Prions from Minimal Components: Requirement of Non-PrP Cofactor
8.5 The Protein X Hypothesis
8.6 Non-proteinaceous Prion Cofactors
8.7 Potential Roles of Cofactors in Prion Formation and Encoding Infectivity
8.8 Additional Roles and Applications for Prion Cofactors
References
Chapter 9: Prion Protein Conversion and Lipids
9.1 Introduction
9.2 Supporting Evidence for the Involvement of Lipids in PrP Conversion
9.3 Biophysical Studies of PrP–Lipid Interaction
9.4 Analysis of PrP–Lipid Interaction Using Density Gradient and Protease Digestion
9.5 The Influence of PrP Mutations on rPrP–Lipid Interaction
9.6 Forming Recombinant Prions with Lipid as a Cofactor
9.7 Possible Roles of Lipid in Forming an Infectious Prion
References
Part IV: Environment and Transmission of Prions
Chapter 10: Prions in the Environment
10.1 Introduction
10.2 Prion Sorption to Soil
10.3 Prion Transport in the Environment
10.4 Degradation and Mitigation of Prions in the Environment
10.5 Do Environmental Factors Influence Prion Incidence?
10.6 Detection of Prions in the Environment
10.7 Conclusion
References
Chapter 11: Environmentally Acquired Transmissible Spongiform Encephalopathy
11.1 Kuru
11.2 Creutzfeldt–Jakob Disease
11.3 Iatrogenic CJD
11.4 The 1970s: Cornea and EEG Depth Electrodes
11.5 The 1980s: Human Growth Hormone (hGH) and Dura Mater Grafts
11.5.1 Human Growth Hormone
11.5.2 Dura Mater
11.6 The 1990s: BSE and vCJD
11.7 The Millennium: Denouement
References
Chapter 12: Risk of Transmission of Creutzfeldt–Jakob Disease by Blood Transfusion
12.1 Introduction
12.2 Experimental Evidence for Prion Disease Transmission by Blood Transfusion
12.2.1 Cellular Prion Protein in Blood
12.2.2 Animal Models
12.2.3 Rodent Models
12.2.4 Primate Models
12.2.5 Sheep Models
12.3 Evidence for vCJD Transmission by Blood Transfusion and Plasma
12.3.1 Secondary Transmission of vCJD by Blood Transfusion
12.3.2 Evidence for vCJD Transmission by Plasma Products
12.4 Evidence for sCJD Transmission by Blood Transfusion and Plasma
12.5 Methods to Detect Prions in Blood and the Prospect of Implementation of a Blood Screening Test for vCJD
12.5.1 The Challenge
12.5.2 Approaches to Sensitive Detection of PrPSc
12.5.3 PrPSc Amplification and Current Blood Test Development
12.5.4 Future Perspectives
12.6 Conclusion
References
Chapter 13: Species Barriers in Prion Disease
13.1 Introduction
13.2 Prion Protein and Prion Species Barriers
13.3 Role of PrP Amino Acid Sequence
13.3.1 Region of PrP Involved in Rodent Species Barriers
13.3.2 Influence of Single Amino Acid Residues
13.3.3 Effect of Prnp Heterozygosity
13.4 Influence of PrP Post-translational Modifications
13.4.1 Glycosylation
13.4.2 GPI Anchor
13.5 Non-PrP Host Factors
13.6 Prion Protein Structure and Prion Species Barriers
13.6.1 Structural Regions of PrPC Implicated in Species Barriers
13.6.2 Effect of Variable PrPSc Conformation
13.7 Molecular Model of Prion Species Barriers
13.7.1 Initial Prion Infection and Species Barriers
13.7.2 Prion Adaptation and Species Barriers
13.8 Intermediate Species and Prion Species Barriers
13.8.1 Altered Properties of BSE After Passage into New Species
13.8.2 CWD Host Range and Species Barriers
References
Part V: Modelling of Prions
Chapter 14: Modeling the Cell Biology of Prions
14.1 Cellular Cultures Supporting TSE Agent Replication
14.2 Cell Models of Pathogenic Mutations in the Prion Protein
14.3 Conclusion
References
Chapter 15: Transgenic Mice Modelling in Prion Diseases
15.1 Introduction
15.2 Host PrP and Susceptibility to TSEs
15.3 Transmission of Agent Within a Host
15.4 Transport into the LRS
15.5 Crossing the Species Barrier and Strain Adaptation
15.6 Defining Strains of TSE Agents
15.7 Mechanisms of Neurodegeneration
15.8 Conclusion
References
Chapter 16: Stem Cell Models in Prion Research
16.1 Introduction
16.2 Stem Cell Models Used in Prion Research
16.3 Stem Cell Models for Elucidating Prion Cell Biology and Function
16.4 Stem Cell Models for Understanding Normal PrP Function in Progenitors
16.5 Murine Stem Cell Models for Studying Prion Disease
16.6 Human Stem Cell Models of Prion Disease
16.6.1 Infectious Disease
16.6.2 Genetic Disease
16.7 Other Stem Cell Models
16.8 Summary
References
Chapter 17: Drosophila Models of Prion Diseases
17.1 The Prion Protein in Disease
17.2 Investigating Biological Processes in Animal Models
17.3 Modeling Prion Diseases in Drosophila
17.3.1 Modeling Neurodegeneration in Flies
17.3.2 Early Fly Models of Prion Disease
17.3.3 Modeling Sporadic Prion Diseases: Neurotoxicity of PrP-WT
17.3.4 Physiological Functions PrP
17.3.5 Topological Variants of PrP
17.3.6 PrP Conformational Dynamics: The PrP Zoo
17.3.7 Protective Residues from Resistant Animals
17.3.8 New Drosophila Models Expressing Human PrP
17.3.8.1 Human PrP Exhibits Heightened Toxicity
17.3.8.2 Examining Protective Amino Acids into Human PrP
17.3.9 Genetic Interactions of PrP in Drosophila
17.3.10 Prion Transmission Studies in Flies
17.4 Concluding Remarks
References
Part VI: Human Prion Diseases and Other Pathologies
Chapter 18: Human Sporadic Prion Diseases
18.1 Introduction
18.2 Individual Types and Subtypes
18.3 Mechanisms of Sporadic Prion Disease Heterogeneity: Old and New
18.4 Phenotypic Heterogeneity and Prion Strains
18.5 Concluding Remarks
References
Chapter 19: Genetics of Prion Disease
19.1 Introduction
19.2 Prion Protein (PrP)
19.3 Molecular Genetics of Prion Disease
19.4 Penetrance
19.5 Other Genes Involved in PrD
19.6 Genetic Prion Disease Subtypes
19.6.1 Creutzfeldt–Jakob Disease (CJD)
19.6.2 Gerstmann–Sträussler–Scheinker Disease (GSS)
19.6.3 Familial Fatal Insomnia (FFI)
19.7 Genotype–Phenotype Correlations
19.8 Transmissibility of Genetic PrD
19.9 PRNP Polymorphisms
19.9.1 Polymorphisms with a Well-Documented Effect on PrD
19.9.2 Polymorphisms with Unclear or No Effect on Disease
19.10 Disease-Associated PRNP Variants
19.11 Octapeptide Repeat Insertions (OPRIs) and Deletions (OPRD)
19.12 Non-OPRI Insertion
19.13 Summary
References
Chapter 20: Glycoform-Selective Prions in Sporadic and Genetic Variably Protease-Sensitive Prionopathies
20.1 Introduction
20.2 Identification of Sporadic Variably Protease-Sensitive Prionopathy
20.2.1 Dominant PK-Sensitive PrPSc
20.2.2 Unique Multiple Ladder-Like Electrophoretic Gel Profile of PK-Resistant PrPSc
20.2.3 PrP-129 Polymorphism-Dependent Variable PK-Resistant PrPSc
20.2.4 Two Sets of PK-Resistant PrPSc Core Fragments
20.2.5 Glycoform-Selective PrPSc Formation
20.3 Identification of Inherited Variably Protease-Sensitive Prionopathy
20.4 Transmissibility of Sporadic and Genetic VPSPr
20.5 PrPSc Seeding Activity of Sporadic and Inherited VPSPr
20.6 Molecular Origin of PrPSc in Sporadic and Genetic VPSPr
20.7 VPSPr and Other Diseases
20.8 Conclusions
References
Chapter 21: The Spectrum of Tau Pathology in Human Prion Disease
21.1 Overview of Tauopathies
21.1.1 Classification of Neurodegenerative Diseases
21.1.2 Tau Protein
21.1.3 Classification of Tau-Related Conditions
21.1.4 Immunomorphology of Pathological Tau Deposition in ‘Main’ and ‘Extracellular Filamentous Deposit-RELATED TAUOPAThies’
21.1.5 Spectrum of Tau Pathology in Other Conditions
21.1.6 How Is Tau Pathology in Prion Diseases to Be Characterized?
21.2 Tau Pathology in Human Prion Diseases
21.2.1 Tau Pathology in Sporadic CJD
21.2.2 Tau Pathology in Acquired CJD
21.2.3 Tau Pathology in Genetic CJD and FFI
21.2.4 Tau Pathology in Dominantly Inherited PrP Cerebral Amyloidoses
21.3 Concluding Remarks
21.3.1 Pathogenesis of Tau Deposition in Human Prion Diseases
21.3.2 Relevance of Tau Protein as Biomarker in Human Prion Diseases
21.3.3 Summary: Classification of Tau Pathology in Human Prion Diseases
21.3.4 Perspectives
References
Chapter 22: Prion Protein Complex with mGluR5 Mediates Amyloid-ß Synaptic Loss in Alzheimer’s Disease
22.1 Introduction
22.2 Relevant Aβ Species in AD
22.3 Aβo Bind to PrPC
22.4 Therapeutic Strategies Blocking the Aβo-PrPC Interaction
22.5 mGluR5 Facilitates Aβo-PrPC-Induced Toxicity
22.6 Targeting mGluR5 with Allosteric Modulators as Novel Therapy for AD
22.7 Future Outlook
References
Chapter 23: Prion and Cancers
23.1 Introduction of Prion Protein
23.2 PrP and Cancers
23.2.1 Breast Cancer
23.2.2 Gastric Cancer
23.2.3 Colorectal Cancers
23.2.4 Pancreatic Ductal Carcinoma
23.2.4.1 GPI-PSS Has a Specific Biological Function
23.2.4.2 Filamin A and PrP Binding
23.2.4.3 Expression of pro-PrP Is a Marker of Poorer Prognosis in Pancreatic Cancer
23.2.4.4 Interacting with Nocth1 Signal Transduction Pathway
23.2.5 PrP and Melanoma
23.3 Conclusion and Future Perspective
References
Chapter 24: Protective Role of Cellular Prion Protein in Tissues Ischemic/Reperfusion Injury
24.1 Introduction
24.2 The Physiological Function of PrPC
24.3 Protective Effect of PrPC on Cerebral Ischemia/Reperfusion Injury
24.4 The Protective Effect of Normal Prion Protein on Cardiac Oxidative Insults
24.5 The Protective Effect of Normal Prion Protein on Renal Ischemia/Reperfusion
24.6 Conclusion
References
Part VII: Animal Prion Diseases
Chapter 25: Bovine Spongiform Encephalopathy
25.1 Introduction
25.2 BSE Epidemics in the UK
25.3 BSE in Europe
25.4 The Impact of the BSE Surveillance System and the Emergence of Atypical BSE Forms
25.5 The Active Surveillance
25.6 The Detection of Atypical BSE Forms by Routine Testing
25.7 Disease Phenotypes of Classical BSE and Atypical Forms of BSE
25.8 Prion Strain Properties in Typical and Atypical BSEs
25.9 On the Origin of BSE
25.10 Cattle BSE and Human Prion Diseases
References
Chapter 26: Classical and Atypical Scrapie in Sheep and Goats
26.1 Overview
26.2 History
26.3 Geographical Distribution and Surveillance
26.4 Prion Protein Gene and Susceptibility
26.5 Epidemiology of Scrapie
26.5.1 Prevalence in the EU
26.5.2 Transmission Routes in Scrapie
26.5.3 Incubation Period
26.5.4 Pathogenesis and Tissue Distribution of PrPSc and/or Infectivity
26.6 Clinical Signs
26.7 Diagnosis of Scrapie
26.7.1 Discriminatory Immunoblot
26.7.2 Histopathology
26.7.3 Immunohistochemistry
26.8 Scrapie Agent Strains
References
Chapter 27: Research Models for Studying Chronic Wasting Disease
27.1 Epidemiology
27.2 Pathogenesis
27.3 Transmission
27.4 Effects of Polymorphic Variation in Cervid Prion Protein Genes on Disease Susceptibility
27.5 Transgenic Mouse Models
27.6 Other Transgenic Models
27.7 CWD Strains
27.8 Cell Culture Models for Studying CWD Prions
References
Part VIII: Yeast Prions
Chapter 28: Introduction to Yeast and Fungal Prions
28.1 Mysterious Non-chromosomal Genetic Elements in Yeast
28.2 Discovery of Yeast Prions and the Three Genetic Criteria
28.3 The [Het-s] Prion of Podospora anserina
28.4 The [PIN+] Prion (Rarely) Seeds Other Prions
28.5 [BETA], an Enzyme-Based Prion
28.6 Amyloids as the Basis of Most Yeast Prions
28.7 Chaperones and Other Cellular Factors Affecting Prion Propagation
28.8 Prion Variants and the Species Barrier
28.9 Perspective
References
Chapter 29: Yeast Prions Are Folded, In-Register Parallel Amyloids Subject to Multiple Anti-prion Systems
29.1 Shuffled Prion Domains of Sup35p or Ure2p Can Still Be Prions
29.2 Solid-State NMR Shows In-Register Parallel Architecture of Yeast Prion Amyloids
29.3 In-Register Parallel Architecture Explains Protein Templating of Conformation
29.4 Biology of Yeast Prions
29.4.1 [Het-s]: Benefit and Detriment
29.4.2 Proposed Benefits of Yeast Prions
29.4.3 Evidence That Yeast Prions Are Diseases
29.5 Anti-prion Systems That Cure Prions in Normal Cells
29.5.1 Btn2 Sequesters Prion Amyloids Promoting Loss by Segregation
29.5.2 Cur1
29.5.3 Proteasomes, Btn2, and Cur1
29.5.4 Hsp104 at Normal Levels Cures Many [PSI+] Prions
29.5.5 Ribosome-Associated Chaperones and [PSI+] 29.5.6 Nonsense-Mediated Decay Proteins (Upf) Have Anti-prion Activity by Complexing with the Prion Protein
29.5.7 Siw14 and Inositol Polyphosphates’ Role in [PSI+] Propagation
29.5.8 Sis1 and Lug1 Limit Toxicity of [PSI+] and [URE3], Respectively
29.6 Perspective
References
Part IX: Diagnosis and Human Prion Surveillance
Chapter 30: Real-Time Quaking-Induced Conversion (QuIC) Assays for the Detection and Diagnosis of Human Prion Diseases
30.1 Introduction
30.2 RT-QuIC
30.3 RT-QuIC for Human Prion Disease Diagnostics
30.4 RT-QuIC for vCJD
30.5 Quantitation by RT-QuIC
30.6 Combining Prion Capture and RT-QuIC
30.7 Technical Considerations
30.8 Biosafety Issues
30.9 Conclusions
References
Chapter 31: Protein Misfolding Cyclic Amplification
31.1 PMCA: A Great Tool to Study Prion Biology
31.2 PMCA Applications to Understand the Mechanism of Prion Transmission, Species Barrier, and Strain Phenomena
31.3 PMCA Applications in Prion Detection and Diagnosis
31.4 PMCA Applications in the Development of Drugs and Prion Decontamination Procedures
31.5 Expanding PMCA Beyond Prion Diseases
31.6 Concluding Remarks
References
Chapter 32: Seeding Activity of Skin Misfolded Proteins as a Biomarker in Prion and Prion-Like Diseases
32.1 Introduction
32.2 Infectivity and Seeding Activity of Misfolded Protein Aggregates in Neurodegenerative Diseases
32.3 Association Between the Skin and the Brain
32.4 Skin PrPSc-Seeding Activity in Prion Diseases
32.5 Skin α-Synuclein Seeding Activity in Parkinson’s Disease and Synucleinopathies
32.6 Tau-Seeding Activity in Alzheimer’s Disease and Tauopathies
32.7 Conclusion
References
Chapter 33: Diagnosis of Prion Disease: Conventional Approaches
33.1 Introduction
33.2 Cerebrospinal Fluid
33.2.1 Routine Tests
33.2.2 14-3-3 Proteins
33.2.3 Tau/p-tau
33.2.4 RT-QuIC
33.2.5 Other CSF Markers
33.2.6 Blood-Based Biomarkers
33.3 Magnetic Resonance Imaging
33.3.1 General Introduction
33.3.2 Test Performance
33.3.3 Changes During the Disease
33.4 EEG
33.5 Molecular Disease Subtype-Specific Diagnosis
33.6 Genetic TSE
33.7 Differential Diagnosis
33.8 Criteria
33.9 Conclusions
References
Chapter 34: Human Prion Disease Surveillance
34.1 Introduction
34.2 Acquired Human Prion Diseases
34.2.1 Kuru
34.2.2 Iatrogenic Creutzfeldt–Jakob Disease
34.2.3 Variant Creutzfeldt–Jakob Disease
34.3 Methods of Surveillance
34.4 Rationale for Surveillance
34.4.1 Zoonotic Threats
34.4.1.1 Variant Creutzfeldt–Jakob Disease
34.4.1.2 Atypical Bovine Spongiform Encephalopathy
34.4.1.3 Chronic Wasting Disease
34.4.1.4 Camel Prion Disease
34.4.2 Increasing Incidence of Prion Disease Over Time
34.4.3 Investigation of Unrecognized Transmission Routes
34.4.4 Investigation of Disease Clusters
34.4.5 Provide a Research Platform
34.5 Conclusions and Recommendations
References
Part X: Treatment
Chapter 35: Overview on Treatment of Prion Diseases and Decontamination of Prions
35.1 Introduction
35.2 Treatment
35.2.1 Treatment: General Principles
35.2.2 Diagnosis
35.2.3 Disease-Modifying Treatment in Humans
35.2.3.1 The Period Up to 2008
35.2.3.2 Quinacrine
35.2.3.3 Pentosan Polysulphate (PPS)
35.2.3.4 Doxycyline
35.2.3.5 PRN 100
35.2.4 Preventative Treatment in Humans
35.2.5 Treatment: Potential Treatment Targets
35.2.6 Treatment: Identifying Possible Treatments
35.2.7 Treatment: Assessing the Efficacy of Potential Treatments in Humans
35.2.8 Treatment: Assessing the Toxicity of Potential Treatments in Humans
35.2.9 Ethical Considerations
35.3 Decontamination
35.3.1 The Background to Decontamination Concerns
35.3.2 Methods of Decontamination
35.3.3 Assessment of Decontamination Methods
References
Chapter 36: Gene Therapy Strategies for Prophylactic and Therapeutic Treatments of Human Prion Diseases
36.1 Overview of Human Prion Diseases
36.2 General Strategies for Development of Therapies Against Prion Diseases
36.3 Reported Gene Therapy Tests Against Prion Diseases in Cell or Animals
36.3.1 Reduction of PrPC Levels by RNAi
36.3.2 Inhibition of PrPSc Replication
36.4 Promising Gene Therapy Strategies Against Prion Diseases
References
Chapter 37: Immunomodulation
37.1 The Immune System and Prion Infection
37.2 In Vitro Studies Using Anti-PrP Antibodies to Block Prion Propagation
37.3 Therapeutic Targeting of Prions: The Challenge of Effectiveness Versus Toxicity
37.4 Passive Immunization for Prion Infection
37.5 Active Vaccination for Prion Infection
37.6 Mucosal Active Immunization
37.7 Conclusions
References
Index