PRIONS replication and transmission different diseases .pptx

prion diseases

1. PRIONS Dr.Madhukar 1 yr PG-Pathology

2. Definition Degenerative diseases of the central nervous system caused by a pathogenic isoform of a normal cell protein

3. Prions:Isoform of normal host protein Normal Protein Protease sensitive Soluble High alpha-helix content Found in brain tissue

4. Disease Causing Prion Protease resistant ,Insoluble Forms amyloid fibrils High beta-pleated sheet conformation

5. Replication and transmission D o not contain nucleic acids, specific mutations in the prion gene permits the folding of a new conformation that is protease resistant. This new conformation then has the capacity over time to associate with other misfolded proteins.

6. PrPC Pathogenic form called prions or PrPSc PrPC -alpha-helix structure, Beta-sheeted form called PrPSc . When PrPC is converted into PrPSc , the new PrPSc are templates that help convert adjacent PrPC into PrPSc . within 1 minute of exposure of PrPC to PrPSc . PrPSc templates, initiating a transformational cascade of nearby PrPC .

7. Accumulation in the cns causes nerve cell injury and eventually death Fluid filled vesicles appear in the dendritic tree of neurons. Enlarge and cause spongiform appearance in brain Transmissible spongiform encephalopathies Vacuolation(spongiform) is the hallmark characteristic.

8. SCRAPIE Disease of sheep Known for at least 200 years Causes scraping of fleece, stumbling, behavioral changes Post mortem exams show loss of neurons in CNS

9. Transmission of scrapie Lambs from healthy flocks acquire the disease when exposed to “ scrapie ” flocks Route of transmission unknown Crosses species lines and infects goats No evidence of infection of humans

10. In sheep- scrapie Bovine Spongiform Encephalopathy - cattle

11. Characteristics of scrapie agent Resistant to formaldehyde, ethanol, protease, heat to 100 degrees C. Resistant to nuclease, uv , ionizing radiation Co-purifies with normal sheep protein

12. Human diseases-TSE IDIOPATHIC- Sporadic Creutzfeldt Jakob disease ( CJD ) ACQUIRED- Iatrogenic CJD - New variant CJD - Kuru GENETIC - Familial CJD - Gerstman straussler scheinker syndrome ( GSS ) - Fatal familial insomnia

13. Pathogenesis and molecular genetics Normal PrP-30-kD Gene encoding PrP-PRNP-a high degree of conservation across species. Mutations in PRNP-Familial forms

14. Normal PrP is a 30-kD cellular protein present in neurons. Disease occurs when the PrP undergoes a conformational change from its normal α-helix-containing isoform ( PrP c ) to an abnormal β-pleated sheet isoform , usually termed PrP sc (for scrapie ) ( Fig. 28-31 ). Associated with the conformational change, PrP acquires resistance to digestion with proteases, such as proteinase K. Accumulation of PrP sc in neural tissue seems to be the cause of the pathology in these diseases, but how this material induces the development of cytoplasmic vacuoles and eventual neuronal death is still unknown. Western blotting of tissue extracts after partial digestion with proteinase K allows detection of PrP sc , which is diagnostic.

15. Creutzfeldts Jakob disease(sporadic) Homozygosity at codon 129 in PrP gene- Risk factor

16. Kuru Disease of New Guinea natives Discovered by D. C. Gajdusek in 1957 100% mortality Experimentally transmitted to chimpanzees Transmitted by ritual cannibalism Many aspects of the disease mimic Creutzfeld -Jacob Disease

17. Creutzfeldt Jakob disease can also have these microscopic changes. Include Neuron loss, astrogliosis Presence of prp sc by immunohistochemistry or western blot. Amyloid plaques of prp sc

18. Gerstmann-straussler-scheinker Amyloid plaques of PrP sc are present Plaques are surrounded by smaller amyloid globules.

19. Characteristics 1. Degenerative nervous system diseases with very long incubation periods (months to years; decades) 2. No inflammatory response 3. Chronic progressive pathology (slow infection) 4. No remissions or recoveries: always fatal 5. “Degenerative” histopathology: amyloid plagues, gliosis 6. No visible virion -like structures by electron microscopy

20. 6. No visible virion -like structures by electron microscopy 8. No interferon production; No interferon sensitivity 9. No infectious nucleic acid demonstrable 10. No antigenicity 11. No alteration in pathogenesis (incubation period, duration, course) by immunosuppression or immunopotentiation

21. 12. No cytopathic effect in infected cells in vitro 13. Varying individual susceptibility to high infecting dose in some host species; Unpredictable ability to cross species lines