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Kuru and Related Diseases 11/29/16 SS Prions Course, 2014. Lecture 1-2: Addi)onal Reading 1. "Deadly Feasts," by Richard Rhodes. Mee)ng 1: Infec)ous prion disease and basics of protein structure. 2. Basic concepts in Protein structure: hVp://www.proteinstructures.com 3. hVp://www.scien)ficamerican.com/ar)cle/the-prion-diseases/ Mee)ng 2: Structural mechanisms of prion transmission. Gene)cs of prions in yeast. 4. Nobel lectures by Gajdusek and Prusiner. 5. Movie (available on YouTube). “Science and Sorcery” Mee)ng 3. Prion mechanisms in neurodegenerave disease. Proposed physiological mechanisms for prion-like conformaonal transi)ons. Mee)ng 4. Intrinsically disordered protein domains and their cellular func)ons. Mani Ramaswami (X8400) [email protected] 2 Daniel CARLETON GAJDUSEK(1923-2008) Physiology and Medicine Nobel Prize in 1976 John Enders Hungarian Rabies and plague Linus Pauling Walter Reed (Joe Smadel) Kuru and related diseases Frank Burnet Viruses Hemorrhagic fever Vincent Zigas and Kuru hVps://www.theguardian.com/science/2009/feb/25/ carleton-gajdusek-obituary 1 11/29/16 Kuru hp://www.youtube.com/watch?v=vw_tClcS6To Kuru: Science and Sorcery 1500 miles Mins 3:07 – 5:30. Cannibalism: 26:45 - 29:00 ; 1:00- 1:10 6 Vincent Zigas, Jack Baker en Carleton Gajdusek onderzoeken kuru-hersenen (in de pan op de eeafel) in Okapa, Nieuw Guinea,1957 Pathology: including lack of inflammaon - Mechanism of infec)on and iden)ty of the pathogen (Contact, food, environment, genes?) Kuru Creutzfeldt-JaKob Disease. Occurs in elderly male or female paents in all communi)es (20 cases were known) - Igor Klatzo, NIH. CJD 7 2 11/29/16 1880s German Physician Robert Koch’s Postulates. 1. The agent must be present in every case of the disease. 2. Inoculaon of pure cultures of the disease should produce disease in animals 3. Cultures of disease agent repurified from infected animals must produce disease again “We tried everything from snakes to bears” - Carleton Gajdusek University of Minnesota and then the Rocky Mountain Labs in Montana. 9 10 Transmission? Disease transmission tests: Kuru to Chimps (Daisy and GeorgeVe) Kigea, an 11-year-old girl from Waisa village who died of kuru. (CJD was also transmiVed) (Michael Alpers) Movie: 29:14-30:17 11 12 3 11/29/16 Scrapie or “tremblante,” the trembling disease -Kuru , Scrapie and CJD are similar. -All three are transmissable.- -Kuru may be transmiVed by endocannibalism. 1700s - 1950s Similar symptoms; Epidemics; Transmissable to other sheep and goats (incubaon )me of 3-4 years in sheep and one year in goats) – Bill Hadlow. William Gordon, a UK Veterinarian: vaccine for a virus (formaldehyde fixed homogenate of infected sheep ssue.). Can be transmiVed to mice, hamsters and many other species. 13 14 Animal prion diseases can be transmiVed by feeding An anthropologist, who traced Kuru back to a single individual in the early 1900s Kuru = CJD = BSE = Scrapie - Downer cale. -Why no inflammaon -Why a long incubaon period 15 -Why and how do different strains arise? 16 4 11/29/16 High Tech Endocannibalism Bovine Spongiform Encephali)s The Guardian Observer, Sunday 22 October 2000 BSE vicKms to get millions: Labour accepts moral case for compensaon 1. Tissue transplantaons - corneal dura membranes Kamal Ahmed and Antony BarneV The Government has agreed a mul)-million-pound compensaon package for 2. Hospital equipment sufferers of the human form of BSE, or mad cow disease, aer agreeing it would be 'morally impossible' to turn them down, The deal, which will delight the 84 families whose lives have been blighted by the disease, is set to be announced on Thursday, 3. Human growth hormone along with the publicaon of Lord Phillips's long-awaited report on the BSE crisis that has stalked Britain since the Eigh)es. Senior Whitehall sources said that, although there were s)ll prac)cal and legal difficul)es that needed to be overcome, the Cabinet commiVee set up to deal with the Phillips report has agreed a no-fault scheme that From ea;ng or contacng infected meat? will pay families hundreds of thousands of pounds. Variant CJD can occur in the very young 13 years + 18 What is the transmissable agent? The Scrapie agent survives: Kuru Infec)on through mortuary feasts (ritual endocannibalism) 1. 30 minutes of boiling. CJD Unknown Mechanism. 2. 60 days of freezing. V-CJD Eang contaminated meat or bloodborne transmission 3. Strong formaldehyde. 4. Dessicaon for 2 years. Iatrogenic CJD Infec)on from surgical ras, equipment or human 5. Intense UV exposure. pituitary derived hormones. 6. Survives electron bombardment that should destroy a genome 1000 )mes smaller than lambda. 19 20 5 11/29/16 What is the transmissable agent? EM images of scrapie-associated fibrils Patricia Merz, 1981 CJD Hamster CJD Human Scrapie The Assay: Inoculum - Inject host – assay disease (short-incubaon model in strain 263K of golden hamsters). Purificaon: Either (a) inhibit necessary components and then add them back (or) (b) separate individual components and test them. 22 Animal prion diseases can be transmiVed by feeding What is the transmissable agent? The Assay: Inoculum - Inject host – assay disease Purificaon: Either (a) inhibit necessary components and then add them back (or) (b) separate individual components and test them. (Inoculum concentraon determines incubaon period) - Downer cale. 23 24 6 11/29/16 Problems using mice Prusiner’s fast hamster assay. 1. Mouse: assays take 12 months. Hamsters show disease in 70-90 days. 60m mice per sample About 300 samples Phenotypes so clear that 4 animals per sample suffice. Inject every 3 months 72000 mice per year; $2 million per year in late 1970s. 80-fold increase in the rate at which frac)ons could be studied! 2. Different mouse strains are different. (Could do in one year – what would have taken a 80 years) 25 26 Prion: Protein Infection (named by Stan Prusiner) Red: Acidic Violet Basic; Green: nonpolar; Blue Polar 22-aa signal pep)de cleaved during translaon 15-aa C-terminal cleaved and glycophosphodylinositol (GPI) anchored (230). 181, 196 N-linked glycosylaon. 5 Octapep)de repeats ((PH/QGGG(G)WGQ) 27 28 7 11/29/16 hVp://www.federaonofscien)sts.org/pmpanels/tse/priprogene.asp Crystallizaon models for prion disease. JS Griffith 1967 and later Carleton Gajdusek Examples: Salts Ethylene diamine tartrate factories Ice 9 (Kurt Vonnegut) 29 30 Prion: Protein Infection (named by Stan Prusiner) 31 32 8 11/29/16 Protein folding and structure (GN Ramachandran’s Phi-Psi plot) How Proteins Fold? – Consider a protein with 100 a.a. • 10100 possible conformaons (avg. of 10 conformaons/a.a.) • If it converts from one conformaon to another in ~10-13 sec then the avg. )me to sample all conformaons would be 1077 years. Cosmic Term: longer than the life of earth/universe 33 34 Anfinson, 1961 Levinthal’s Paradox • However, in vivo, proteins fold in 10-1- 103 seconds, a mismatch of >98 orders of magnitude • Conclusion: Folding is not random. It is determinis)c (directed) 35 36 9 11/29/16 Hydrophobic groups are usually buried 37 38 Secondary structure Key concepts in protein structure Alpha helices Beta sheets Sequence Secondary structures (helices and beta sheets) Motifs (specific functional organization of secondary structure units) Domains (autonomous folded unit) Full protein (can be multi domain and/or multisubunit) (local structures) (between sequences that are separated) 39 40 10 11/29/16 Structural motifs and Protein Folds Ribbon representations Helix Bundle TIM Barrel Different beta sheet motifs β-hairpin 41 42 No new folds have been discovered since 2008! Domains and multidomain proteins Red bars – show total number of known folds in each year (2012 to the leu) - Maxes out at about 1300. 44 11 11/29/16 45 46 The precision and reproducibility of protein-folding processes within cells is such that protein molecules of the same amino acid sequence have 3-D conformaons sufficiently homogenous to form macroscopic crystals. This property is absent from most other polymers: • polyesters, • celluloses, • polysccharides, • fay acids, • long DNA 47 12 .
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