The enigma of slow viruses. Facts and artefacts.

1. Introduction: subacute spongiform virus encephalopathies from the perspective of a neuroscientist.- 2. The molecular biology of the slow viruses.- 2.1. The search for the virus-specific nucleic acid.- 2.1.1. Radiation experiments.- 2.1.2. Fruitless attempts to isolate scrapie-specific infectious nucleic acid.- 2.2. The prion protein.- 2.2.1. The purification of the PrP 27-30, PrP 33-35SC and PrP 33-35C.- 2.2.1.1. Strategies used to purify the scrapie virus and scrapie specific protein.- 2.2.1.2. Purification of the PrP27-30.- 2.2.1.3. PrP proteins are disease-specific for the whole group of unconventional slow virus disorders.- 2.2.1.4. PrP 33-35SC and PrP 33-35C.- 2.2.2. The structure of the PrP proteins.- 2.2.2.1. N-terminal sequence of the PrP.- 2.2.2.2. The secondary structure of the PrP.- 2.2.3. Postranslational modifications of the PrP.- 2.2.4. Functional studies of the PrP proteins.- 2.2.5. The scrapie associated fibrils or prion rods.- 2.2.5.1. The chemical composition of SAF.- 2.3. The structure of the gene encoding PrP 33-35 (Prn-p) in different species.- 2.3.1. The hamster Prn-p gene.- 2.3.2. The murine Prn-p gene.- 2.3.3. The rat Prn-p gene.- 2.3.4. The human Prn-p gene (PRNP).- 2.3.5. The ovine and bovine Prn-p gene.- 2.3.6. The avian analogue of the Prn-p gene.- 2.3.7. The linkage of genes controlling the incubation period and susceptibility to scrapie and Creutzfeldt-Jakob disease (CJD) to the gene encoding PrP 33-35 (Prn-p).- 2.3.7.1. Prn-i and Sinc in mice.- 2.3.7.2. Prn-i and Sip gene in sheep.- 2.3.8. The linkage of Gerstmann-Straussler-Scheinker syndrome (GSSS) to the PrP (PRNP) gene.- 2.3.9. Familial CJD.- 2.3.10. The association of CJD cases of Eastern European origin and in Sephardic Jews with a mutation of the PrP gene at codon 200.- 2.3.11 Other PrP gene mutations associated with sporadic and familial CJD cases.- 2.3.12 A 0.15kb insertion within the PrP gene observed with CJD and GSSS cases.- 2.3.13 The codon 178 mutation in familial CJD.- 2.4. The models of slow viruses.- 2.4.1. Strains of scrapie virus.- 2.4.2. The prion-only hypothesis.- 2.4.3. Virino and conventional virus hypothesis.- 3. The pathogenesis of slow virus infection.- 3.1. The general sequence of the pathogenetic events.- 3.2. The role of the spleen.- 3.3. The role of the spleen in neuroinvasion.- 3.4. The role of viremia.- 3.5. The role of macrophages in scrapie infection.- 3.6. The neural spread of infectivity from the spleen to the central nervous system.- 3.7. The neural spread of infectivity within the central nervous system.- 3.8. Biochemistry and histochemistry of slow virus infections.- 3.8.1. Neurotransmitters alterations.- 3.8.1.1. Cholinergic system.- 3.8.1.2. Monoaminergic systems.- 3.8.1.3. Histaminergic system.- 3.8.1.4. GABAergic system.- 3.8.2. Oxydative and lysosomal enzymes.- 3.8.2. Immunology of slow virus infections.- 3.8.2.1. Autoantibodies against neuroflament proteins.- 3.8.2.2. Increased concentration of IgG in serum of scrapie- affected sheep.- 4. Neuropathology of slow virus diseases Ill.- 4.1. Natural scrapie.- 4.2. Kuru.- 4.3. Creutzfeldt-Jakob disease (CJD).- 4.3.1. Introduction.- 4.3.2. Classifications.- 4.3.3. Classical CJD.- 4.3.4. Ataxic form of CJD.- 4.3.5. Gerstmann-Straussler-Scheinker (GSS) syndrome.- 4.3.6. Panencephalopathic form of CJD.- 4.3.7. Amyotrophic form of CJD.- 4.3.8. CJD and other neurological disorders.- 4.4. Elements of neuropathology of slow virus disorders.- 4.4.1. Spongiform vacuoles.- 4.4.1.1. Introduction.- 4.4.1.2. Distribution of vacuoles within grey and white matter: lesion profile.- 4.4.1.3. Ultrastructure of vacuoles.- 4.4.1.3.1. Creutzfeldt-Jakob disease (CJD).- 4.4.1.3.2. Scrapie, bovine spongiform encephalopathy (BSE) and chronic wasting disease.- 4.4.1.3.3. Ultrastructure of intramyelin vacuoles in the panencephalopathic type of CJD and other types of subacute spongiform virus encephalopathies.- 4.4.1.4. Morphogenesis of spongiform changes.- 4.4.2. Astrocytic reaction.- 4.4.2.1. Introduction.- 4.4.2.2. Kuru, Creutzfeldt-Jakob disease and Gerstmann- Straussler-Scheinker syndrome.- 4.4.2.2.1. Kuru.- 4.4.2.2.2. Creutzfeldt-Jakob disease (CJD) and Gerstmann- Straussler-Scheinker syndrome (GSSS).- 4.4.2.2.3. The involvement of astrocytes in formation of amyloid plaques.- 4.4.2.4. Scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease.- 4.4.2.5. The blood-brain-barrier in slow virus diseases.- 4.4.2.6 The particular forms of astrocytic reaction in unconventional slow virus diseases.- 4.4.2.7. Expression of glial fibrillary acidic protein (GFAP).- 4.4.3. The neuropathology of amyloid plaque.- 4.4.3.1. Kuru.- 4.4.3.2. Creutzfeld-Jakob-disease CJD.- 4.4.3.3. Gerstmann-Straussler-Scheinker (GSS) syndrome.- 4.4.3.4. Scrapie and bovine spongiform encephalopathy and chronic wasting disease.- 4.4.3.5. The biology of amyloid plaques.- 4.4.3.5.1. The biology of amyloid plaques the correlation between the number of amyloid plaques and strain of virus, inoculation route and aging.- 4.4.3.5.2. The immunohistochemistry of amyloid plaques.- 4.4.3.5.3. The relation of amyloid plaques to neuroaxonal dystrophy.- 4.4.4. Tubulovesicular structures.- 4.4.4.1. Introduction.- 4.4.4.2. Virus-like particles of unknown significance.- 4.4.3. Tubulovesicular structures.- 4.4.5. Neuroaxonal dystrophy.- 4.4.5.1. Neuroaxonal dystrophy: a common form of neuronal degeneration.- 4.4.5.2. Neuroaxonal dystrophy in subacute spongiform virus encephalopathies.- 4.4.6. Different forms of neuronal degeneration in slow virus disorders.- 4.4.6.1. The degeneration and neuronal loss.- 4.4.6.2. Intranuclear eosinophilic inclusions.- 4.4.6.3. Spiroplasma-like inclusions.- 4.4.6.4. Cerebellar lamellar bodies.- 4.4.6.5. Intraneuronal inclusions in bovine spongiform encephalopathy.- 4.4.6.6. Autophagic vacuoles in Creutzfeldt-Jakob disease and scrapie.- 5. Final conclusions.- Addendum.- References.

Topic: Prion Diseases and Protein Misfolding
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences