Infectious Agents and Slow Degenerative Diseases of the CNSViral Disea - PDF document

Infectious Agents and Slow Degenerative
Infectious Agents and Slow Degenerative Diseases of the CNSViral DiseasesMeasles (SubacuteSclerosingPanencephalitis)HIV (HIV-D, HIV dementia)HTLV-I MyelopathyJC and BK (Progressive multifocalleukoencephalopathy)Rubella panencephalitisRabiesCanine distemper virusPrionDiseasesScrapieMad CowCreutzfeldt-JakobFatal familial insomniaGerstmann-StrausslerScheinkerBrain HistologyPapua New GuineaDisease affectsthe TribeWalking Sticks3Spongiform EncephalopathiesMid 1930s -vaccine prepared against Louping-illInfectious encephalomyelitis of SheepViral disease spread by ticks (Flavivirus)Formalin-inactivated viral vaccine prepared from sheep brainNo adverse effects caused by vaccination for

2 yearsSubsequently, some sheep herds de
2 yearsSubsequently, some sheep herds developed ScrapieRealized that Scrapiewas an infectious agent found in some batches of Louping-ill vaccineGordon, W.S., PhD. Advances in Veterinary Research. The Veterinary Record; 1946 November 23. Presented at the National Veterinary Medical Association of Great Britain and Ireland Annual Congress, 1946. Suggestion that Scrapieis an Infectious Disease“Slow Viral Diseases”-?Human PrionDiseasesAbout 1 yr9 extendedfamilies identifiedInheritance of amutation in the PrPgeneTrouble sleeping anddisturbance of theautonomic nervoussystem. Followed bydementia and lossof coordinationFatalfamilialinsomnia2-6 yrs50 extendedfamilies identifiedInherita

nce of amutation in the PrPgeneLoss of
nce of amutation in the PrPgeneLoss of coordinationfollowed by dementiaGerstmann-Straussler-ScheinkerdiseaseUsually 1 yrbut as short as 1 mo and aslong as 10 yrsSporadic1/1,000,000Inherited100 extended families identifiedInfectious80 cases identifiedUsually unknown(Sporadic disease)15% of cases involvean inherited mutationin the PrPgeneRarely infectionthrough contaminatedsurgical instrumentor organ transplantDementia followed by loss of coordinationCreutzfeldt-Jakob Disease3 mo -1 yr2600cases identified in Papua New GuineaInfection (Cannibilism)Loss of coordination followed by dementiaKuruDISEASE COURSEDISTRIBUTIONACQUSITIONSYMPTOMSDISEASECreutzfeldt-Jakob Disease•Most

common human TSE -about 1 case/million/
common human TSE -about 1 case/million/yr•Three forms traditionally recognized1.sCJD-sporadic, about 85% of cases2.fCJD-familial, about 10% of cases3.iCJD-iatrogenic, about 5% of cases•In 1996 a new variant emerged in the U.K. -vCJDAssociated with eating beef infected with BSE agent (Mad Cow)In contrast with traditional forms of CJD, vCJDstrikes young adultsCrossed species barrierCreutzfeldt-Jakob DiseaseBSE Epidemic in UK4vCJDin U.S.•Extremely small, proteinaceousinfectious particle•Resistant to DNAseand RNAse•Resistant to limited proteolysis•Resistant to chemical agents that inactivate conventional virusesSearch for the Agent (PrusinerLab)Genetic mutations in CJD and other Prio

nDiseasesP102LP105LA117VY145-stopM129VD
nDiseasesP102LP105LA117VY145-stopM129VD178NV180LE20KR206HV210IQ217RN171SE219KM232ROctapeptiderepeat(P/Q)HGGG(G/-)WGQH3H4Signal SequenceLipidH2 change conformationPrionDiseaseHow Does Conformational Conversion Occur?Introduction of infectious pathogenic form (Scrapie, BSE) Heritable mutations that promote spontaneous conversion (CJD)SolubleInsolubleIncrease in -strand content6Plaques Produced by Hamster Prionsin Transgenic MiceRequired for Disease ProgressionPrPGene KnockoutNot susceptible to priondiseasePossibly more prone to seizuresWhat is Normal PrPGlycoprotein ~250 amino acidsMembrane associated through a C-terminal glycosyphosphatidylinositol(GPI) linkageRole in mem

brane trafficinghas been proposed -possi
brane trafficinghas been proposed -possibly involved in some endocyticpathwaysKnockout mice develop and behave normally, but perhaps prone to seizuresInteracts with laminin, which plays a role in cell adhesion and neuriteformationAlso interacts with the lamininreceptor resulting in internalization of membrane-bound PrPBinds Cu-may have an antioxidant function that promotes neuron survivalAbundant in brain -also detected in: spleen, lymph node, lung, heart, kidney, skeletal muscle, uterus, adrenal gland, parotid gland, intestine, and mammary gland.Prionsingested and absorbed by intestines (PeyersPatches)Gains access to lymphoid fluids and bloodDeposited in lymphoid tissues where it ampl

ifies through conformational conversionA
ifies through conformational conversionAmplified prionsdeposited in brain -perhaps crosses blood-brain barrier or migrates by axonal transportReplicates in brain -toxicity resulting in neuronal cell deathCurrent View of PrionDisease DevelopmentCriticisms of the PrionHypothesis are being AddressedThere are different strains of Prions•Differ in incubation time, clinical features, and neuropathology•How are ‘Strains’developed without evolution of nucleic acid genomes?Can conformational transition be observed in vitro?A recombinant purified Prionhas not been shown to induce diseaseConformation A‘Strain A’Fast ConversionConformation B‘Strain B’Slower ConversionHypothesis -Conformational S