CLINICAL ASPECTS OF BIOCHEMISTRY NEURODEGENERATIVE DISEASES Prion diseases Alzheimer's disease.

Slides:



Advertisements
Similar presentations
Distinctive characteristics
Advertisements

Defective Interfering RNAs DI RNAs are formed by deletion and recombination during viral RNA replication They require helper virus to replicate and to.
1 Chapter 50 Molecular Basis of Prion Diseases Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
Rhiannon Aguilar HONR299J Final Presentation Spring 2014.
Prion Disease Transmissible spongiform encephalopathy (TSE)
Presented by Béla Reiz Supervisor: Dr. Liang Li
Prions MICR 401 Group 8: Ben Saiyasombat 10/30/2012 Department of Biology and Microbiology.
PRIONS Defn: small proteinaceous infectious particles that resist inactivation by procedures that modify viruses and nucleic acids.
ALZHEIMER'S DISEASE (AD)
Mouse Prion Protein Domain PrP( ) Andreas Razen Geometric Computations in Molecular Biology 2 May 2007.
Osman Adil Jamshed Chem th December, Prions Prions are misfolded form of proteins classified as infectious pathogens. Responsible for fatal.
1 Transmissible Spongiform Encephalopathies. 2 Kuru Since the early 1900’s the Fore people of New Guinea have honored their dead by cooking and consuming.
Transmissible Spongiform Encephalopathies (Prion disorders)
Prions Fact or Science Fiction?. Stanley Prusiner, 1982 Born in Des Moines, Ia. Suggested that spongiform encephalopathies in animals and humans are caused.
L and D isomers of amino acids. Ionization state as a function of pH.
Prions Alicia Arguelles, Jerry Wang May 4, What are prions? proteinaceous infectious particle an infectious agent made only of protein, containing.
Mad Cow Disease. Effects of Mad Cow disease Mad cow disease, or bovine spongiform encephalopathy (BSE), is a fatal brain disorder that occurs in cattle.
© Elsevier, 2011.Principles of Molecular Virology Subviral Agents Satellites and viroids – parasites of parasites! Prions - infectious protein molecules.
Disorders caused by pathological conformation of proteins
Prion Diseases Microbes and Society Fall What is a Prion? Prion- small proteinaceous infectious particles which resist inactivation by procedures.
Mad Cow Disease The Past History of Mad Cow Disease
Viruses Chapter Nature of Viruses All viruses have same basic structure -Nucleic acid core surrounded by capsid Nucleic acid can be DNA or RNA;
Prion biology problem space: Mad cows, itchy sheep and protein structure.
Holly Allen CREUTZFELDT-JAKOB DISEASE.  Human equivalent of mad cow disease  Rare, degenerative, fatal disease  Approximately 1 case per million per.
BIOCHEMISTRY DR AMENA RAHIM. Structure of Elastin It is a connective tissue protein Rubber like properties Elastin & glycoprotein microfibrils are present.
PRIONS THE INFECTIOUS PROTEINS
 Laura Manuelidis argues a difference between a TSE AGENT and a PrP PATTERN.  Her research uses new techniques to attempt to define the differences.
Transmissible Spongiform Encephalopathies (TSEs) a.k.a. Prion Diseases Transmissible  can be spread Spongiform  resembling a sponge Encephalopathies.
Transmissible Spongiform Encephalopathy Prion Protein Diseases Lisa Kennedy, Dylan Bradford, Madi Hoagland Henefield, Anders Ohman Advisor: Dr. Todd Livdahl.
Prions: Proteins Gone Bad
By : Amirah nu’aimi Sharifah Nurul Hanim TASK 2 – DISCUSS THE EXAMPLE OF PROTEIN FOLDING DISEASE BY STATING THE MECHANISM.
PRIONS PETER H. RUSSELL, BVSc, PhD, FRCPath, MRCVS Department of Pathology and Infectious Diseases, The Royal Veterinary College, Royal College Street,
Creutzfeldt-Jakob’s disease or Prion Disease or Mad Cow disease It belongs to a group of neurodegenerative diseases called Transmissible Spongiform Encephalopathy.
Protein Misfolding Can Have Deadly Consequences Yu Tiantian Li Yihan.
PRIONS Kalina Estrada TA: Yu-Chen Hwang Thursday, 7-8pm.
----protein folding can have deadly consequences
12 August 2003 CJD Update Latest facts, figures & findings Jonathan P Clewley TSE Unit, Virus Reference Division, Centre for Infections 20 May 2005.
Taylor Goldbeck.  Professor and Head of Neuropathology at Yale- Department of Surgery and Faculty of Neurosciences and Virology  Focuses on dementia.
Proteins as Pathogens Stanley B. Prusiner, MD The Nobel Prize in Physiology or Medicine Presented by Shannon S. Rickner-Schmidt.
PRIONS 221.
Characterizing and Classifying Viruses, Viroids, and Prions.
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Attachment, Penetration, and Uncoating Figure
Viruses, Viroids, and Prions
The History of Chronic Wasting Disease Dr. Trent Bollinger, CCWHC One World, One Health Symposium Sept. 29, 2004.
Beyond Viruses…Beyond Viroids…
Prions “Scrapie” “mad cow disease” Nobel Prize 1997
Microbes and Diseases Chapter 02. CREUTZFELDT-JAKOB DISEASE Prion.
Bovine Spongiform Encephalopathy, a.k.a. “Mad cow disease” usdaaphis-475x248.jpg.
Creutzfeldt-Jakob Disease Atif Chohan & Alex Brown.
The Prion Diseases Stanley B. Prusiner.. Description & History Fifteen years ago I evoked a good deal of skepticism when I proposed that the infectious.
Today’s Lecture: Bringing the disease to YOU! From the 1950s to NOW From Papua New Guinea to the U.S.A.
Biochemistry of neurodegenerative diseases and prions Alice Skoumalová.
Prion diseases (transmissible spongiform encephalopathies) Dr. Mohammad Shakeeb, MD Specialist in clinical pathology/Microbiology and immunology.
CLINICAL CORRELATIONS
(Bovine spongiform encephalopathy)
CLINICAL CORRELATIONS
Petra Jenišová Veronika Plačková Magdaléna Trojanová
Investigations into Prionic Mutations Mutated Prion Protein (PrPSc)
Prion proteins THE 'protein only' hypothesis' states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such.
Disease Transmission and Species Barrier
Lecture Week 11 Medical Microbiology SBM 2044
Rabies virus and Prion Dongli Pan
PRIONS.
Lecture Week 11 Medical Microbiology SBM 2044
CLINICAL CORRELATIONS
Persistant viral infections of the central nervous system
Deadly Conformations—Protein Misfolding in Prion Disease
What are Prions? A microscopic protein particle similar to a virus but lacking nucleic acid.
Presentation transcript:

CLINICAL ASPECTS OF BIOCHEMISTRY NEURODEGENERATIVE DISEASES Prion diseases Alzheimer's disease

SOME PRION DISEASES TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SpeciesTransmission ScrapieSheepInfection Bovine spongiform encephalopathy (BSE) CowInfection (contaminated feed) KuruHumanInfection (cannibalism) Creutzfeldt-Jakob disease Iatrogenic Familial Sporadic New variant Human Infection (growth hormone etc.) Germline mutations of PrP gene Somatic mutations of PrP gene or spontaneous conversion Infection (eating beef?) Gertmann-Straussler- Scheinker disease (GSS) humanGermline mutations of PrP gene Fatal familial insomnia (FFI)HumanGermline mutations of PrP gene

SPONGIFORM BRAIN TISSUE From Prusiner (1998)

HOW CAN PROTEINACEOUS PARTICLE BE INFECTIOUS? (a)May contain "shielded" nucleic acid? (b)Proteins specify own aa sequence? (c)Normal cells carry a gene that encodes PrP, and the product is changed to a different conformation by the infectious particle?

THE PRION HYPOTHESIS TSEs occur when the normal ‘cellular’ form of the prion protein (PrP c ) is converted to the abnormal form (PrP sc ). PrP c and PrP sc differ in conformation. The conversion is ‘autocatalytic’ - PrP sc facilitates the conversion of more PrP c to PrP sc.

1. The nature of PrP c and PrP sc 2.Conversion of PrP c to PrP sc 3.Inherited TSEs 4.Species specificity and species barriers 5.Strains 6.Normal function; role in disease 7.Doppel 8.BSE and nvCJD 9.Therapies? TSEs - MAIN TOPICS

Normal (PrP c ) and abnormal (PrP s ) forms of prion protein PrP c Precursor ~ 250 amino acids. Mature PrP c ~ 210 aas Hydrophobic glycoprotein GPI anchor (glucosyl phosphatidyl inositol) NMR structure - C-terminal end  -helical, N-terminal end unordered PrP sc Same sequence and postranslational modifications as PrP c Different conformation - more  -sheet Tends to form insoluble aggregates More resistant to proteolysis than PrP c Insoluble PrP sc ( in amyloid plaques) not infectious?

PrP C PrP Sc PrP C PrP Sc -PK +PK PrP Sc IS RESISTANT TO PROTEOLYSIS Based on Priola (2001)

STRUCTURE OF THE HUMAN PRION PROTEIN Globular domain Based on Rivera-Milla et al (2003)

HYPOTHETICAL MODELS FOR PrP c AND PrP sc Based on Prusiner (1998)

beta sheet alpha helix

PrP Sc CAN CONVERT PrP C TO PrP Sc IN VITRO Based on Priola (2001)

TWO MODELS FOR CONVERSION OF PrP C TO PrP Sc (a) PrP C PrP Sc (b) Etc ~6 Very slowfast

INHERITED FORMS OF CJD, GSS, FFI etc Mutations may stabilise PrP sc conformation e.g. P102L in GSS [when this was engineered into mice they developed 'scrapie') Met/Val 129 polymorphism in man - Val homozygotes more susceptible to CJD? Met homozygotes more susceptible to nvCJD?

SOME POINT MUTATIONS IN THE PrP GENE THAT CAUSE HUMAN PRION DISEASE PositionNormalMutant 102ProLeu 105ProLeu 145AlaStop 178AspAsn 180ValIle 200GluLys Based on Priola (2001)

SPECIES BARRIERS TO TRANSFER OF PrP Sc Sequence differences between PrP from different species may provide (and explain?) some barrier to infection - but incomplete. E.g. Mouse  mouse transfer gives more rapid infection than mouse  hamster etc. But, mouse  hamster  hamster gives faster infection, Homologous PrP Sc is better at converting PrP C than heterologous

STRAINS OF PRION DISEASES Scrapie occurs as about 20 different strains (differentiated by time taken to infect mice and different behavioural effects). CJD occurs as 2-4 different strains. BSE only one. May be explicable in terms of different conformations, but the more strains the more far-fetched this explanation. The biggest problem with the Prusiner model? For 2 CJD strains - evidence for different conformations (pattern of proteolysis)

DIFFERENT PrP Sc STRAINS - DIFFERENT CONFORMATIONS Based on Priola (2001) -PK +PK

WHY DOES PrP Sc CAUSE DISEASE? Possible explanations include: Neurotoxic Deposits disrupt cells Deposits disrupt intercellular contacts (synapses etc) Loss of PrP C NORMAL FUNCTION OF PRP C Not clear; knockout mice lacking PrP are not seriously abnormal Possible roles in cell signalling and in processing copper ions have been suggested

DOPPEL (Dpl) A PrP-like protein (~25% sequence identity but shorter). Gene close to PrP gene - could explain variable effect of PrP knockouts Involvement in prion diseases? Based on Behrens & Aguzzi (2002)

ANNUAL INCIDENCE OF BSE IN THE UK 40,000 30,000 20,000 10,000 Number of BSE cases Year of epidemic

nvCJD incidence

nvCJD incidence ,000 30,000 20,000 10,000 Number of BSE cases Year of epidemic

CJD - POSSIBLE THERAPIES Drugs that stabilise PrP C (stabilise helical conformation) Drugs that inhibit aggregation & amyloid (  sheet) formation Immunization against PrP C or PrP Sc