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1. Introduction
2. Degenerative diseases of the CNS
3. Human prion diseases
4. Bioassays in hamsters and discovery of PrP
5. Structures of prion protein isoforms
6. PrP gene mutations cause inherited prion diseases
7. PrP - crystal of 28d / SHaPrP 29-232
8. X-ray studies of PrP - 28d antibody fragments
9. NMR and X-ray structures of PrP
10. Prion protein gene structure and protein products
11. Two dimensional crystals of PrP 27-31
12. Image reconstruction results
13. Beta-helices exist as trimers
14. Refined PrPSc model overlaid onto crystal lattice
15. Building an amyloid fiber
16. Tertiary structures of PrPC and PrPSc
17. Some features of prion formation
18. Energetics of PrPC conversion into PrPSc
19. Synthetic prions
20. A transgenic host sensitive to prion infection
21. Inoculation of beta-rich isoforms of MoPrP(89-143)
22. Making amyloid is a correlate of infectivity
23. Analysis of MoPrP(89-230)
24. Polymerization of recMoPrP(89-230)
25. Matching the mouse to the inoculum
26. Tg9949 mice develop prion disease
27. Protease resistant PrP in inoculated Tg9949
28. Neurohistology of pons of Tg9949 mice
29. Astrocytic gliosis in inoculated Tg9949 mice
30. Serial transmission of synthetic SMP1 prions
31. Second passage of synthetic prions in Tg9950
32. Serial passage of synthetic prions to other mice
33. Protease K resistant PrP from SMP1 prions
34. Pons of Tg9949 passaged in wt FVB mice
35. Synthetic mammalian prions
36. Heterocyclic pharmacotherapies for prion disease
37. Proposed PrPSc replication cycle
38. Pyridinyl-based therapies
39. Compound-60 analogues
40. Pyridinyl-based therapies - Q168
41. Pyridinyl-based therapies - new leads
42. Pyridinyl-based therapies - T215
43. Pyridinyl-based therapies - thienopyridines
44. Acridine-based therapies
45. Acridine and phenothiazine-based therapies
46. Acridine-based therapies - quinacrine
47. Treatment with quinacrine cures ScN2a cells
48. Could acridine dimers be more potent?
49. Cellular efficacy correlates with linker length
50. Efficacy and cytotoxicity are influenced by linker
51. Bis-acridine is ten-fold more potent than quinacrine
52. Bis-acridine and PrP co-localize
53. Survival of sCJD patients treated with quinacrine
54. Treatment of mice inoculated with RML prions
55. Concepts from the discovery of prions
56. Age-dependent human neurodegenerative diseases
57. ND diseases are autosomal dominant

Topics Covered

• Understanding the biophysical aspects of a disease of protein misfolding
• Structural studies of PrPc and PrPsc
• The development of synthetic mammalian prions and the proof of their infectivity and serial transmissibility
• Heterocyclic pharmacotherapies for prion disease
• Pyridinyl based therapies and structure based design
• Serendipitous discovery of acridines as anti-prion agents
• Bisacridines as potent inhibitors of prion replication in cell culture
• The relationship between the prion diseases and other diseases of protein misfolding

Links

Series:

• Protein Folding, Aggregation and Design

Categories:

• Biochemistry
• Clinical Practice
• Neuroscience

Therapeutic Areas:

• Neurology

Talk Citation

Publication History

• Published on October 1, 2007
• Archived on April 17, 2016

Financial Disclosures

• Prof. Fred Cohen has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.