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Structural disorder, prions, am y loid s and pol y glutamin e diseases

Structural disorder, prions, am y loid s and pol y glutamin e diseases. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. Am y loid diseases. Am y loid diseases : “traditional” classification. s ystemic vs. tissue-specific

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Structural disorder, prions, am y loid s and pol y glutamin e diseases

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  1. Structural disorder, prions, amyloids and polyglutaminediseases Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary

  2. Amyloid diseases

  3. Amyloid diseases: “traditional”classification systemic vs. tissue-specific juvenile vs. adult or old inherited vs. spontaneous primary vs. secondary protein vs. peptide mass in kgs vs.almost negligible (globular vs. IUP) so what is common ???

  4. Amyloid fibrils • 10nm • straight • stable • tinctorial properties (Congo red) • cross-b

  5. Symptoms fall into two broad classes Systemic cases - organ failure (heart, liver, kidney) Tissue-specific cases - cognitive impairment (dementia, often with psychiatric symptoms) - loss of coordination of movement - neurodegeneration

  6. Amyloid diseases

  7. Amyloid diseases: modern classification  protein misfolding diseases • Protein (AL, ATTR, ALys) • Cause (spontaneous, mutation, induced) • Mechanism (loss or gain of function)

  8. Alzheimer’sdisease AD plaque Neurofibrillarytangle (PHF)

  9. Amyloid precursor protein (APP) (TACE, ADAM10) (PSEN)

  10. „Lag-phase” and „seeding” (1D crystal growth) „Seeding” Exponential growth Long incubation time Chen et al. (2001) JMB 311, 173

  11. Familial systemic amyloidosis: Lysozyme mutants D67H I56T

  12. Wild type Ile56Thr Asp67His Reduced stability of amyloidogenic mutants Booth et al. (1997) Nature 385, 787

  13. 123I-SAP scintigraphy liver normal kidney Pepys

  14. Huntington’sdisease (Huntingtin) MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNG… ATGGCGACCCTGGAAAAGCTGATGAAGGCCTTCGAGTCCCTCAAGTCCTTCCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCCGCCACCGCCGCCGCCGCCGCCGCCGCCTCCTCAGCTTCCTCAGCCGCCGCCGCAGGCACAGCCGCTGCTGCCTCAGCCGCAGCCGCCCCCGCCGCCGCCCCCGCCGCCACCCGGCCCGGCTGTGGCTGAGGAGCCGCTGCACCGACCAAAGAAAGAACTTTCAGCTACCAAGAAAGACC…

  15. PolyQ expansion: polymorphisms Wells (1996) JBC 271, 2875

  16. Huntingtin inclusionsin neuronalnuclei Perutz (1999) TiBS 24, 58

  17. Cause of disease? Loss of function Gain of function

  18. Age of onset, DRPLA CAG repeat units Anticipation in polyQ-disease inheritance - dynamic mutation, mutable mutation - Tsuji (1997) Int. Med. 36, 3

  19. Prion diseases (TSE) HUMAN kuru CJD (Creutzfeldt-Jakob) GSS (Gerstmann,Straussler, Sheinker) FFI ANIMAL SCRAPIE sheep BSE bovine TME mink CWD deer FSE cat

  20. rapid cognitive impairment (dementia) • movementdisorders • spongiform degeneration

  21. Chronology • XVIII c. scrapie • 1920 CJD (heritable) • 1939 scrapie transmissible • 1954 scrapie: „slow virus” • 1959 kuru resembles CJD • 1959 kuru resembles scrapie • 1966 kuru  chimpanzee transmissionGAJDUSEK • 1982 „prion” Prusiner • 1986 BSE (first case) • 1997 Nobel prizePRUSINER

  22. Ancient scrapie? ` ، disease = like rash flee Wickner (2005) Science 309, 864

  23. Chronology • XVIII c. scrapie • 1920 CJD (heritable) • 1939 scrapie transmissible • 1954 scrapie: „slow virus” • 1959 kuru resembles CJD • 1959 kuru resembles scrapie • 1966 kuru  chimpanzee transmissionGAJDUSEK • 1982 „prion” Prusiner • 1986 BSE (first case) • 1997 Nobel prizePRUSINER

  24. infected proteinase K Stanley B. Prusiner • strange pathogen (resistance to UV, heat etc…) • purification • transmission to mouse (incubation time 150-300 days) • 1975-77: transmission tohamster (70 days)

  25. Infectious protein ? • no DNA • PrPsc and infectivity purify together • properties of PrPsc match those of prion • PrP: encoded by the host • inherited forms: mutations of PrP gene 1982 proteinaceous infectious PRION

  26. Amyloid: mad-cow disease Patholopgical prion: structure of PrPC GPI * * * (PHGGGWGQ)5 * * * * P102L * * P107L * A127GAAA*AGAVVGGLGG133

  27. Extension of the prion concept: physiological prions • Two yeast genetic element[URE3], [PSI+] • dominant, non-Mendelian inheritance (meiois) • non-chromosomal (cytoplasmic) • metastable (curable) • selective advantage ?

  28. Sup35p (translation release factor 3, eRF3) normal Sup35p = [psi-] prion Sup35p = [PSI+] Suppression of nonsense mutations

  29. Sup35p: eukaryotic translation release factor3 MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD HVSIIFMGHVDA........

  30. Prion (amyloid) form of Sup35 promotes translation read-through

  31. Sup35: disorder and modularity

  32. Sup35: disorder and modularity

  33. „Lag-phase” and „seeding” (1D crystal growth) „Seeding” Exponential growth Long incubation time Chen et al. (2001) JMB 311, 173

  34. Prion infection: „cross-seeding” „Cross-seeding” Exponential growth Long incubation time Chen et al. (2001) JMB 311, 173

  35. Extension of prion concept: prions and memory?

  36. Hippocampus and memory

  37. Aplysia californica GSW reflex LTF habituation, sensitisation Eric Kandel

  38. 5 x 5-HT Aplysia neuronal CPEB is involved in LTF Si et al. (2004) Cell 115, 893

  39. Aplysia neuronal CPEB is a prion Si et al. (2004) Cell 115, 879

  40. The structure of amyloid(ogenic) proteins Needs to be addressed: - structure of amyloidogenic protein - structure of intermediate - structure of amyloid itself

  41. Structure ofamyloidogenic proteins Globular: lysoyzme transthyretin (TTR) insulin b2-microglobulin IDP: a-synuclein tau protein polyQ regions prion domains

  42. Structure:lysozyme D67H I56T

  43. Structure: polyQ

  44. Structural ensemble of a-synuclein (NMR paramagnetic relaxation enhancement) Dedmon et al. (2005) JACS 127, 476

  45. Structure ofamyloidogenic proteins Globular: lysoyzme transthyretin (TTR) insulin b2-microglobulin IDP: a-synuclein tau protein polyQ regions prion domains

  46. Structure ofamyloidogenic proteins Globular: partial unfolding lysoyzme transthyretin (TTR) insulin b2-microglobulin IDP: partial folding a-synuclein tau protein polyQ regions prion domains

  47. Structure of the intermediate ? temp. temp.

  48. Partially ordered amyloid precursors Uversky and Fink (2005) BBA 1698, 131

  49. The common denominator: polyproline II helix? SH3-PPII Wikipedia

  50. PPII in a-synuclein (ROA) Syme (2002) EJB 269, 148

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