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Disorders caused by protein pathologic conformation

Disorders caused by protein pathologic conformation. Jan ILLNER Alice Skoumalová. Theoretical model of folding (hierarchic): local secondary structure formation tertiary structure formation (subdomains, domains) stable conformation. Thermodynamic model:

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Disorders caused by protein pathologic conformation

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  1. Disorders caused by protein pathologic conformation Jan ILLNER Alice Skoumalová

  2. Theoretical model of folding (hierarchic): • local secondary structure formation • tertiary structure formation (subdomains, domains) • stable conformation • Thermodynamic model: • Protein is folded to gain the lowest levels of his free energy: • native state • There are other alternative • conformations: • different protein function • pathologic protein

  3. Abnormal tertiary structure of specific protein causes pathologic conformation α-helix β-sheet Conformational change • the starting point is the natural protein folded in the native and active conformation • normal protein is rich in α-helix conformation (folded structure) • the end-point is the same protein adopting prevalent β-sheet structure • it is disease-associated protein (misfolded structure) Aggregation Gain of toxic activity Neurodegenerative diseases Loss of biological function

  4. Protein with pathologic conformation Mutation (familiar) Error in folding process (sporadic) Identification Degradation(protein quality control system) 1. Chaperones 2. Ubiquitine proteasome system

  5. Molecular chaperones Hsp 70 - new synthetised proteins: (heat shock protein) Chaperonines - misfolded proteins: Hsp 60

  6. DNA Ubiquitin Ribosome RNA ATP Chaperones Nativeprotein Misfolded protein Aggregate/fibrillar amyloid Chaperones Proteasome Accumulation(Amyloidoses) Degradedprotein Gainof toxicity (Alzheimer´sdisease) Lossof protein function(Cysticfibrosis)

  7. Protein pathologic conformationconsequences: Gain of toxicity neurodegenerative disorders - chronic, progressive diseases loss of neurones • pathologic protein accumulation • aggregate generation (Alzheimer´s, Parkinson´s, Hungtington´sdisease) Loss of biological function • cystic fibrosis - genemutation for chloride channel Accumulation amyloidoses - fibrils are not toxic but they are insoluble

  8. Amyloid fibril structure • straight, unbranched, diameters in the range of 8-16 nm • composed of two to sixprotofilaments • rich in a type of β-sheet structure (the β-sheets are perpendicular to the fibril axis and bind together by the hydrogen bonds)

  9. Molecular factors in amyloid formation • proteinmisfolding is central to amyloid formation • protein stability (the resistance of the folded conformation to misfolding) is an important factor in determining susceptibility to amyloid formation Destabilizing factors: 1.Extreme environments in the body, such as acidic cell compartments 2. Proteolytic removal of portion of a protein by an endogenous protease 3. Mutations that alter primary structure 4. Interaction with lipid bilayers

  10. Amyloid formation

  11. Protein quality control in the cell

  12. Alzheimer´s disease

  13. Characterization: • progressive neurodegenerative disease • the most common form of dementia associated with aging • loss of cognitive function • Diagnosis: • histological findings in brain tissue (senile plaques, neurofibrillary tangles) • clinical criteria: neuropsychological tests • magnetic resonance imaging • laboratory • problematical diagnostics: symptoms are common for other dementias or are • similar with aging • Therapy: impossible to stop only slow down timely diagnostics • Causation:unclear; β-amyloid peptide accumulation, oxidative stress ??? • Aims of research: to produce a laboratory test (from blood or liquor) that could be used for better diagnostics

  14. Types and prevalence of AD in population sporadic familiar • most • later onset • unknown causations • less than 2 % • onset at the age of 65

  15. Pathological signs of AD • Amyloid (senile) plaques • protein β-amyloid fibrils (Aβ) • abnormal processing of APP (amyloid precursor protein) • Neurofibrillary tangles • hyperphosphorylated protein tau

  16. Role of amyloid β in pathogenesis of AD Effort in research: decrease Aβ42 accumulation by inhibition of β- or γ-secretase, support α-secretase or increase Aβ42 degradation by specific antibodies

  17. Role of oxidative stress in pathogenesis of AD pathologic changes in the brain oxidative stress

  18. Prions and prion disorders

  19. Prion definition • Prions are proteinaceous transmissible pathogenesresponsible for a series of fatal neurodegenerative disorders • Creutzfeld´s-Jakob´sdisease • kuru • bovine spongioform encephalopathy • Prion (proteinaceous infectious particle);analogy for virion • It is a type of infectious agent that does not carry the genetic information in nucleic acid! • Prions are proteins withthe pathological conformation that are believed to infect and propagate the conformational changes of the native proteins into the abnormally structured form

  20. PrPC PrPC(cellular) Normal protein Transmembrane glycoprotein (neurons, lymphocytes); its function is unknown; it binds Cu2+ Dominant secondary structure α-helix Easily soluble Monomeric, easily digested by proteases Encoded by a gene designed PRNP located on the chromosome 20 PrPSc PrPSc (scrapie) Abnormal protein, disease-producing protein The same amino acid sequence (primary structure) Dominant secondary structure β-sheet Insoluble Multimeric, resistant to digestion by proteases When PrPSc comes in contact with PrPC, it converts the PrPC into more of itself These molecules bind to each other forming aggregates

  21. Molecular models of the structures of: PrPCPrPSc Predominantly α-helix (3x) β-sheet (40%), α-helix (30%)

  22. Prion aggregates

  23. Prion disorders: rare neurodegenerative diseases sporadic familiar transmissible • in 6th or 7th decade • rapidly progressive • CJD • inherited • mutations in the PrP gene that favour the transition from the cellular to the pathologic form of PrP • rare • BSE, kuru • Creutzfeldt´s-Jakob´sdisease • the most common prion disease • death in less than a year • Kuru disease • propagation in New Guinea natives • ritualistic cannibalism

  24. Prion transmission Direct contact with infected tissue Consumption of affected tissue • cannibalism, kuru • consume material from animal infected with BSE, vCJD • from instruments used for brain surgery • corneal grafts • electrode implants How can prion make their way through the gut and into the brain? Hypothesis: Prions circumvent the normal process of intestinal absorption by passing into the GALT (gut-associated lymphoid tissue)

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