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The Pathological Protein

The Pathological Protein . Chapter 6 & 7 . Chapter 6: Family Curses . The Daughter of the “H” Family Her family was plagued with prion disease through the generations After close examination of her family and her symptoms Motor Neuron decay in the Cerebellum

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The Pathological Protein

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  1. The Pathological Protein Chapter 6 & 7

  2. Chapter 6: Family Curses • The Daughter of the “H” Family • Her family was plagued with prion disease through the generations • After close examination of her family and her symptoms • Motor Neuron decay in the Cerebellum • GSS- Gerstmann-Straussler-Scheinker • Amyloid plaque build up • A genetic prion disease • Coding for Disease • PrP gene of GSS • Noticed a single point mutation • Codon 102 P->L • Different folding pattern • Found all over the world • Hsiao’s transgenic mice • 13 different point mutations found to cause prion diseases by the 1990s

  3. Chapter 6: Family Curses • The Family That Couldn’t Sleep • Fatal Familial Insomnia • Silvano S. • At least 30 members of hisfamilyhad FFI • Lugaresi and FFI • Damage to the Thalamus • Codon 178 D->N • One Codon, TwoDiseases • Condon 178: one mutation, but twodiseases? • Answer: Condon 129 • Polymorphism: Methionine or Valine • M/M and M/V = FFI • V/V = CJD

  4. Chapter 6: Family Curses • The Strain Puzzle • Transgenic Mice: Support for Prion Theory • The Virus Theory advocates • The Strain Enigma • The need of genetics • Species-specific prion • Virino • Explaining Strain with Prions • 1. Fact that Prp is a glycoprotein • 2. Proteinase K • FFI = 19,000 D CJD= 21,000 D • Hyper and Drowsy strains of mink • Degradation rate • All the same Prpsc proteins

  5. Chapter 7: On the Prion Proving Ground • Power of Yeast • A simpler organism can help give validity to phenomenon • Mendelian genetics: the deviation from the pattern • Prions • {PSI} & {URE3} • Prions of Yeast • {URE3}, URE2, & URE2-mutant • Ureidosuccinate • {URE3} & URE2-mutant found to be identical • URE2 -> {URE3} or URE mutation • Wickner and the cure • Did not follow traditional infection pattern • Three main criteria of prions • {PSI} and SUP35 • Liming Li’s artificial prion • No need for genetic material for prions

  6. Chapter 7: On the Prion Proving Ground • From Helix to Sheet • PrP-sen & PrP-res • NMR and X-ray cryst. • Proved only conformational difference • Alpha Helix vs. Beta Sheets • The Propagation theories • “The Nucleated Polymerization model” • PrP: Protein of the Cell Membrane • One Big Problem: Test tube PrPsc was not infective • Cofactors or Cold fusion? • GAGs • Self vs Non-self • Robert G. Rohwer • Bruce Cesebro

  7. Chapter 7: On the Prion Proving Ground • The Copper Connection • What is the purpose PrP……..who knows. • Copper? • Connection first found in Test tube experiment • More concrete evidence found in neuron copper sulfide test • Transgenic mice: wild type had over 20X more copper than null • Only minor role in the long run • Double Trouble • PrP-null getting a Prion disease? • Prnd and the PrP promoter

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