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Overview Nature of the infectious particle in TSE TSE strains Role of PrP C in disease Potential therapeutic targets Implications for other neurodegenerative.

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Presentation on theme: "Overview Nature of the infectious particle in TSE TSE strains Role of PrP C in disease Potential therapeutic targets Implications for other neurodegenerative."— Presentation transcript:

1 Overview Nature of the infectious particle in TSE TSE strains Role of PrP C in disease Potential therapeutic targets Implications for other neurodegenerative diseases

2 Prion Diseases: Transmissible Spongiform Encephalopathies Fatal neurodegenerative diseases in man and mammals Transmissible under natural and experimental conditions Lengthy incubation period with no conventional host response Characteristic neuropathology with spongiform change in grey matter Associated with conversion of PrP C to PrP Sc

3 Prion diseases of humans and animals Scrapie in sheep and goats Transmissible mink encephalopathy Chronic wasting disease in deer & elk Bovine spongiform encephalopathy Feline spongiform encephalopathy Kuru Creutzfeldt-Jakob disease Gerstmann-Straussler- Scheinker disease Fatal familial insomnia Variant Creutzfeldt- Jakob disease

4 Protein-only version of the prion hypothesis Prions are transmissible particles that are devoid of nucleic acid and seem to be composed entirely of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a post-translational process during which it acquires a high beta-sheet content. Prusiner SB, Proc Natl Acad Sci USA 1998;95:

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6 Role of PrP C in TSE PrP C is required for disease propagation and neuropathology PrP C with GPI anchor to cell membrane transduces or potentiates the neurotoxicity of TSE infection Tg PrP null mice do not propagate TSE infectivity Tg mice expressing only anchorless PrP C can propagate TSE infectivity, but with greatly reduced neuropathology and clinical effects

7 Infectious particle in prion diseases Nonfibrillar particles between kDa (mass equivalent to ~14-28 PrP molecules) Other molecular constituents? Cofactors for infectivity – sulphated GAG or nucleic acids?

8 PrP res Isotype by Western blot Treatment with proteinase K results in N-terminal truncation of PrP res Distinct isotypes of PrP res characterize different forms of CJD Isotypes differ in extent of truncation and degree of glycosylation site occupancy

9 Multiple conformations of PrP Sc ? In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc. (Prusiner) Is there evidence for heritable structural diversity in different prion diseases?

10 PRNP codon 129 genotype frequencies MMMVVV Normal 37%51%12% population Sporadic CJD71%15%14% vCJD100% - -

11 Idiopathic human prion diseases

12 Do different PrP res types replicate with fidelity in vitro? Soto et al, 2005 When human PrP C is converted to PrP res in a PMCA reaction the product has both the conformation and the glycosylation ratio of the in-put PrP res

13 Cellular co-factors & conversion: mammalian RNA Mammalian brain extracts contain RNA that stimulate the conversion of PrP C to PrP Sc in a modified PMCA reaction (Deleault et al, Nature 2003;425: )

14 Conservation of PrP res isotype following transmission to mice Telling et al 1996

15 Conservation of targeting following transmission to mice FFI transmitted to Tg(MHu2M)Prnp 0/0 mice Thalamic pathology fCJD E200K transmitted to Tg(MHu2M)Prnp 0/0 mice Cortical pathology Telling et al 1996

16 Aspects of PrP Sc structure that might encipher strain properties Extent of structural re-arrangement (conversion to -sheet) at the N-terminus. Presence of methionine or valine at codon 129 Presence or absence of bound divalent cations (Cu 2+ ) Extent of of asparagine-linked glycosylation site occupancy Composition and complexity of attached glycans

17 Pathogenic mechanism If we accept the centrality of of the conversion of PrP C to PrP Sc in the pathogenic process, then there are in principle three possible alternatives: –The loss of an essential function of PrP C –The acquisition of a toxic function by PrP Sc –Production of toxic intermediate or by-product

18 Neurodegenerative mechanism Hope 2000

19 Problems with anti-TSE therapy Which compound(s) to use? What route of delivery to use? Is peripheral treatment required? How long to treat?

20 Approaches to treatment of TSE Prevention of PrP C conversion Dissolution of PrP Sc aggregates Enhanced PrP Sc clearance Neuronal rescue?

21 Strategies to prevent PrP C conversion Inhibition of expression by RNA interference Binding to site(s) for physiological ligands, resulting in PrP C clustering and internalisation from cell surface

22 Compounds with in vivo anti- TSE activity Class/compoundExample Sulphonated dyesCongo red Sulphated glycanspentosan polysulphate Cyclic tetrapyrrolesporphyrins Polyene antibioticsamphotericin B Quinolenesquinacrine Metal chelatorspenicillamine Tetracyclinesdoxycyline

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24 Detection of PrP Sc in the peripheral tissues in CJD sCJD CNS PNS Optic nerve Retina Olfactory epithelium vCJD CNS PNS Optic nerve Retina Appendix Lymph node Peyers patches Tonsil Spleen Thymus Wadsworth et al, (2001), Lancet, 358, pp Head et al, (2004), American Journal of Pathology, 164, pp143-53

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26 Neurodegenerative disease and aberrant protein deposition Classical neuropathology identifies abnormal histological structures which are diagnostic for particular conditions. Nuclear and cytoplasmic inclusion bodies and extracellular amyloid deposits Proteinaceous, fibrillar, and rich in -pleated sheet secondary structure Fatal attractions between abnormally folded forms of specific normal cellular proteins resulting in specific neurodegenerative diseases A common feature of Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and prion diseases

27 Neurodegenerative diseases associated with abnormal protein conformations (toxic gain of function) DiseaseGene product Alzheimers diseaseAPP and A Creutzfeldt-Jakob diseasePrP c and PrP Sc Parkinsons disease synuclein Huntingdons diseaseHuntingtin Machado-Joseph disease Ataxin 3 (SCA 3)

28 Neuronal vulnerability to toxic gain of function Neurones are post-mitotic cells which cannot be replaced (liable to damage by increasing DNA mutations?) Unique metabolic demands - some neurones have to maintain an axon over 1m in length Functional plasticity Environment subject to control by many other structures, including astrocytes and the blood-brain barrier

29 Review Nature of the infectious particle in TSE TSE strains Role of PrP C in disease Potential therapeutic targets Implications for other neurodegenerative diseases


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