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TSE SE present presented ed by by Himadri Himadri & M & Markus kus Source: Markus Gerstel, 2008, Balliol College TSE OMG we are all going to die!!!11 Transmissible Spongiform Encephalopathy An expedition into death,

  1. TSE SE present presented ed by by Himadri Himadri & M & Markus kus Source: Markus Gerstel, 2008, Balliol College

  2. TSE ”OMG we are all going to die!!!11”

  3. Transmissible Spongiform Encephalopathy An expedition into death, depression, and zombies

  4. Taxonomy Protein Misfolding Diseases Proteopathies Alzheimers ALS Huntinton's Disease Amyloid β peptide Superoxide dismutase Huntingtin Cystic Fibrosis TSE Cftr Prion diseases Source: Soto, 2006, Prions, the new biology of proteins, table 11.1

  5. Taxonomy Protein Misfolding Diseases Proteopathies Alzheimers ALS Huntinton's Disease Amyloid β peptide Superoxide dismutase Huntingtin Cystic Fibrosis TSE Cftr Prion diseases Source: Soto, 2006, Prions, the new biology of proteins, table 11.1

  6. Transmissible Spongiform Encephalopathy Prion diseases GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats

  7. Transmissible Spongiform Encephalopathy Prion diseases GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats

  8. Gerstmann-Sträussler-Schenker (GSS) syndrome Symptoms: Dementia (loss of cognitive ability) Ataxia, Myoclonus (loss of muscle control, twitching) Duration: 1-15 years after symptoms, starts usually at 25-50 yrs Cause: familial, autosomal dominant inheritance GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 77ff, 88

  9. Gerstmann-Sträussler-Schenker (GSS) syndrome Symptoms: Dementia (loss of cognitive ability) Ataxia, Myoclonus (loss of muscle control, twitching) Duration: 1-15 years after symptoms, and then you die Cause: familial, autosomal dominant inheritance GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 77ff, 88

  10. Fatal Familial Insomnia (FFI) Symptoms: Insomnia, Hallucinations, complete inability to sleep, weight loss, Dementia Duration: 7-15 months after symptoms Cause: familial, autosomal dominant inheritance GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 87f; Soto, 2006, Prions, the new biology of proteins, p. 4

  11. Fatal Familial Insomnia (FFI) Symptoms: Insomnia, Hallucinations, complete inability to sleep, weight loss, Dementia Duration: 7-15 months after symptoms, and then you die Cause: familial, autosomal dominant inheritance GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 87f; Soto, 2006, Prions, the new biology of proteins, p. 4

  12. Kuru Symptoms: Ataxia, then: Dementia Duration: 2-24 months, after incubation period 2-20 years Cause: eating brains GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 40ff

  13. Kuru ”Within the highlander population the disease has been virtually eliminated since the cessation of the handling and eating of the brains of deceased relatives” – Claudio Soto, Prions, the new Biology of Proteins , p. 3 GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 40ff

  14. Bovine Spongiform Encephalopathy (BSE) Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, after incubation period 4-5 years Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices GSS kuru FFI secondary: feeding cattle with cattle meat bone meal humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. Off. Int. Epiz. 2003, 22 (1) 297-310

  17. Bovine Spongiform Encephalopathy (BSE) Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, and then they die Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices GSS kuru FFI secondary: feeding cattle with cattle meat bone meal humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., 2003, Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. OIE 22(1): 297-310

  18. Bovine Spongiform Encephalopathy (BSE) Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, and then they die, and then you die Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices GSS kuru FFI secondary: feeding cattle with cattle meat bone meal humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., 2003, Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. OIE 22(1): 297-310

  19. Transmissible Spongiform Encephalopathy Prion diseases GSS kuru FFI humans humans humans BSE CJD cattle humans scrapie CWD FSE sheep deer cats

  20. Creutzfeldt-Jakob Disease Did you ever... ...then... ...and... have parents? get surgery? eat beef? do nothing? Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

  21. Creutzfeldt-Jakob Disease Did you ever... ...then... ...and... have parents? get surgery? eat beef? do nothing? ”...lifelong vegetarian who had no family history, never had surgery, had never worked on a farm, or in a butcher's shop, and who had never left Britain” – Fatal Protein, p. 91 Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

  22. Creutzfeldt-Jakob Disease Did you ever... ...then... ...and... have parents? get fCJD get surgery? get iCJD eat beef? get vCJD do nothing? get sCJD ”...lifelong vegetarian who had no family history, never had surgery, had never worked on a farm, or in a butcher's shop, and who had never left Britain” – Fatal Protein, p. 91 Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

  23. Creutzfeldt-Jakob Disease Did you ever... ...then... ...and... have parents? get fCJD die slowly get surgery? get iCJD die early eat beef? get vCJD die later do nothing? get sCJD die quickly R I P Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

  24. … brains! Observations: ● Spongiform degeneration diffuse or focally clustered small, round vacuoles ● Neuronal apoptosis cause of brain malfunction ● Astrogliosis increase in astrocytes due to neuron destruction ● Amyloid deposition plaques of PrP Sc R I P Source: Soto, 2006, Prions, the new biology of proteins, p. 8

  25. Neuronal Apoptosis ER stress ER Ca 2+ Caspase-12 Caspase-12 activation Caspase-3 activation Apoptosis R I P Source: inspired by Soto, 2006, Prions, the new biology of proteins, fig. 7.2 p. 77

  26. Neuronal Apoptosis ER stress ER Death receptor Ca 2+ Mitochontrial stress Caspase-12 Caspase-12 activation Caspase-3 activation Apoptosis R I P Source: inspired by Soto, 2006, Prions, the new biology of proteins, fig. 7.2 p. 77

  27. Three Hypotheses ● Virus extremely slow acting virus infectious means bacteria or viruses But: too small, to resistant to UV and radiation ● Virino compact and highly resistant protein coat around a small informational molecule But: no evidence ● Protein-only pr oteinaceous i nfectious particle – pri on infectious misfolded protein that replicates by misfolding other proteins R I P Source: Soto, 2006, Prions, the new biology of proteins, p. 13ff

  28. Meet PrP – The Prion Protein PrP Sc PrP C Bovine prion protein residues 23-230 prion exhibiting β-sheet structure R I P Source: The Protein Data Bank, ID: 1DX0; Lopez-Garcia, F., Zahn, R., Riek, R., Wuthrich, K.: NMR Structure of the Bovine Prion Protein Proc.Nat.Acad.Sci.USA 97 pp. 8334 (2000); PrPSc image from http://www.biophys.uni-duesseldorf.de/research/prions/index.html

  29. Meet PrP – The Prion Protein In short: PrP Sc facilitates production of PrP Sc from PrP C PrP C PrP Sc fibrilous PrP Sc -structures block reverse conformational change strong bonding of β-sheets results in protease resistance R I P Source: Alberts et al., Molecular Biology of The Cell, 5 th edition, p. 397

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