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Complete info about Prions and related diseases in animals/Humans

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  1. 1. Proteins are fundamental components of all living cells: The hemoglobin Hormones Antibodies Enzymes Actin and myosin,Keratin Collagen …………… “All are proteins”
  2. 2. Proteins  Primary structures  Secondary structure  The most common shapes are the alpha helix and the beta conformation. Secondary Structure α helix β sheet + + variable loops = Tertiary Structure
  3. 3. Secondary structure of a protein Examples of alpha helices and beta sheets
  4. 4.  Only one of these many ways allows the protein to function properly.  Too much of a misfolded protein could be worse than too little of a normally folded one.  This is because a misfolded protein can actually poison the cells around it. Why do proteins fold ?
  5. 5. To cary out their function a protein should fold and attain stability
  6. 6. Transmissibility in 1943 when a population of Scottish sheep was inoculated against a common virus with a formalin extract of lymphoid tissue unknowingly derieved from an animal with scrapie after two years nearly 10 of flock developed Scrapie. GORDON 1946 History of Prions
  7. 7.  Sometimes a scientific discovery shakes the confidence of scientists, making them question whether they truly understand nature's "ground rules."  That's exactly what prions have done to scientists, understanding of the ground rules for infectious diseases. Confusion created by Prions Contd…
  8. 8.  After some years a clinically and pathologically Similar human disease KURU meaning “trembling”.  Lead to hypotheses that the nature of infectious agent ranging from a Replicating polysaccharide to Nucleo protein complex  Filterable, formalin treatment didn’t completely abolish infectivity.
  9. 9. Kuru victims- lose the ability to walk, talk, and see Gajdusek
  10. 10. Scrapie  The prototype (18th century in England)  Causes intense itching to make the sheep scrape off their wool  A natural progressive brain disease  Evidence of transmissibility during vaccination
  11. 11. Dr Stanely Prusiner The Prion Hypothesis “ a replicating protein”
  12. 12.  The molecular nature was a mystery till 15 years  Stanley Prusiner showed its assosciation with a specific Protein.  Activity of prion was inactivated by proteinase K, Diethylpyrocarbonate, Urea, Phenol and SDS.  Activity not lost by nuclease treatments or UV irrradiation. Nature of prions Contd..
  13. 13.  PrP is a 250 amino-acid residue glycosylated protein connected to GPI-anchor.  The primary structure of PrP encoded by the gene of a normal was found to be identical to that encoded by a c DNA from a scrapie infected animal  Ab against prP 27-30 identified the prp protein in the brain of uninfected animals and in many tissues as a 33-35KDa glycosylated species,termed PrPC.
  14. 14. The normal protein is called  PrPC-alpha helices.  PrPSc- forscrapie  Beta helices Nomenclature of Prion Protein  PrPSc has the ability to convert PrPc to Itself
  15. 15. Conformational Differences between PrPc and PrPsc PrPc PrPsc Monomeric Multimeric Soluble Insoluble Protease sensitive Protease resistant Predominantly alpha helices Beta helices
  16. 16. A protein of identical size was also observed in scrapie-infected brain extracts. Limited proteinase k digestion Prpc completely degraded. Prpsc a protein in infected Brain was only partially cleaved 66 aa on –NH2 terminus Yields PrP 27-30
  17. 17.  Proteinaceous infectious particles  Abnormal proteins that have an affinity for the CNS  Very highly resistant to heating (survive routine autoclaving)  Not sensitive to irradiation  Not destroyed by enzymes that damage DNA or RNA  Sensitive to protein denaturing agents Characteristic features of Prions Contd…
  18. 18.  Abnormal prions contact and change the shapes of other normal prions in the nerve cell.  The nerve cell tries to get rid of them  When the cell dies, the abnormal prions are released to infect other cells.  Large, sponge-like holes are left where many cells die.
  19. 19.  Sheep - Scrapie Spongiform Encephalopathy.  Chronic Wasting Disease -Elk, Deer  Cow - Bovine spongiform encephalopaty  Human - Creutzfeldt-Jakobs Disease Kind of Disease they cause in Different animals
  20. 20. Cerebral cortex : loss of memory and mental acuity,visual impairment (CJD) Thalamus : Damage to the thalamus may result in insomnia (FFI) Cerebellum : problems to coordinate body movements and difficulties to walk (kuru, GSS) Brain stem : In the mad cow disease (BSE), the brain stem is affected
  21. 21. Prion replication theories 2) Splitting theory 1) The nucleated polymerization theory Jarret and Lansbury, (Cell 1993)
  22. 22. PrPC PrPSC PrPC
  23. 23. PrPsc fibrils
  24. 24. Plaque
  25. 25. How are these abnormal proteins acquired?  Spontaneous conversion  A mutation in the prion gene in a brain cell  Inherit the abnormal gene from your parents  Ingestion of the protein  Humans could be accidentally infected with the protein (iatrogenic) Needles, Tissue, Pituitary extracts
  26. 26. How are Prion Diseses Usually Diagnosed ?  There is no blood test to detect the presence of prions  Currently there are two laboratory methods to confirm a diagnosis: – Microscopic examination of the brain tissue – Special staining and microscopic techniques to detect the partially-proteinase resistant form of the prion (PrP) protein. SDS PAGE
  27. 27. Bovine Spongiform Encephalopathy First noted in UK in early 1985 Animals fed rendered sheep meal Prevalence peaked at about 35,000 animals 2 to 4 year incubation time (longer?) Loss of motor control, other neural control
  28. 28.  Following the onset of clinical signs, the animals condition deteriorates until it either dies or is destroyed.  This process usually takes from 2 weeks to 6 months.  Most cases in Great Britain (where it was first detected) have occurred in dairy cows between 3 to 6 years of age. How Does it Progress?
  29. 29. There are three phases of BSE in cattle:  The first phase: Low infectivity rate, and the cow does not pose a large threat to humans at this level  The second phase: Symptoms are not evident, but the infectivity level is very high The prion agent is abundant in both the spinal chord and the brain – the cow is a risk to public health  The third phase:
  30. 30. Cattle affected by BSE experience progressive degeneration of the nervous system.
  31. 31. Affected animals may display changes in temperament, nervousness or aggression,abnormal posture……….
  32. 32. How to identify the affected Cattle
  33. 33.  Prions in cattle are mainly from the carcasses of scrapie-infected sheep  Infected sheep brains and other sheep byproducts infected with scrapie is used to feed cattle with the meat and bone meal  The prions are concentrated in the brain, and spinal cord of these animals How Prions transmitted from Sheep to Cattle?
  34. 34.  UK still had about 200 BSE cases in 2005. Portugal and Spain are still increasing in numbers of BSE cases.
  35. 35. Cattle on the way to Grave yard
  36. 36. Impact of mad cow disease on economy
  37. 37.  The shock wave ripples across the world.  Import bans imposed by many other nations have cut deeply into the US beef industry  Direct and indirect economic activity from the industry adds up to $188 billion annually, making it the largest portion of the nation's food and fiber industry in US  Japan which had been the largest importer of US beef - continues to demand that all US cattle scheduled for export be tested for BSE  One challenge is that the animals have to be killed in order to test for BSE.
  38. 38. Mad Cow Disease in Humans  When cattle brains and other cattle byproducts infected with BSE are ingested by humans, there is a risk of developing the Creutzfeldt-Jakob Disease
  39. 39. How did BSE Transfer to Humans  Sheep with Scrapie used in Meat and Bone Meal (MBM) – known as “Offal”  MBM fed to cattle  Infected Beef eaten by humans  Not affected by cooking
  40. 40. Creutzfeldt-Jakob disease (CJD)  Identified by Creutzfeldt and Jakob (1920)  A progressive fatal neurodegenerative disease of unknown cause  Characterized by seizures, massive incoordination, dementia  Incidence about 1/1,000,000
  41. 41. CJD is classified into 2 forms:  Classic CJD & Variant CJD  Classic CJD can be transmitted to other species, however other animals cannot carry it. Variant Creutzfeldtt-Jakob Disease (vCJD), is caused by the consumption of BSE infected meat products  First 10 cases of variant CJD were observed in 1996, ten years after the outbreak of BSE in the UK Variant CJD seems to affect mostly young patients
  42. 42. New Treatment for vCJD?  A 19-year-old male from Belfast has been treated with pentosan polysulphate by injection into the brain
  43. 43. There is no Cure for Mad Cow Disease & Creutzfeldt-Jakob Disease Prevention is the only available option
  44. 44. What is the risk?
  45. 45. Mad cow disease in india Epidemic that struck Europe had its roots in India Lancet
  46. 46. “thank you”