A New Dawn of Understanding

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The Physiology of Prions

• A New Dawn of Understanding
• Proteins

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PrionsPrP PrPc - Structure

• normal cells express cellular PrP (glycoprotein)
  on their surface in the plasma membrane
• Sequence of amino acids surface protein
• A normal PrPc protein is recycled from the
  endosomal compartment to the cell surface for use
  as a copper receptor(?) this cycling between
  the cell surface and an endocytic compartment is
  a process that is mediated by clathrin-coated
  pits and a PrPC receptor

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Prion Structure cont

• PrPc has a mostly in the "alpha helix
  conformation with small beta sheets.
• The shape is very structurally weak, and
  therefore, normal cellular prions can be broken
  down quite easily by normal means as most
  proteins - by heat, or proteases, etc.

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PrP Physiology?

• function is still unknown - may be involved in
  cell-to-cell communication?
• researchers have found that PrPc on the surface
  of nerve cells, can interact with other molecules
  to relay signals arriving from outside the cell,
  a vital process in the nervous system known as
  signal transduction.''

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PrPc Physiology cont

• Suggest PrP are on the surface dendrites (the
  long, spindly arms of nerve cells that receive
  incoming signals)
• Not clearly determined how but an incoming
  message stimulates the prions triggering
  chemical intermediaries within the cell in a
  cascade of biochemical events results in
  movement of a signal from outside to inside the
  cell activation of enzymes capable of changing
  how the nerve cell communicates with other cells

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Prion Physiology cont

• Indications that protein synthesis, localized to
  the dendrites, enables a function known as
  long-term facilitation, which is a strengthening
  of synaptic connections

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PrP physiology cont

• Some researchers speculate that prions are not
  needed for routine functions but somehow enable
  the nervous system to fine-tune itself at the
  cellular level
• Other researchers
• prion-like properties to a mechanism involved in
  maintaining memory
• involvement with the immune system
• function in circadian rhythm and sleep regulation
  

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Prion Physiology cont more theories

• Researchers have reason to suspect that in the
  presence of prions, the increased diversity of a
  cell's protein repertoire may offer the cell a
  means to deal with ever-changing environmental
  conditions, all without affecting DNA and
  altering the genetic code prions may help to
  shape the course of evolution
• Huge opportunities exist for continued research
  into prion structure and physiology

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Abnormal Prion

• same amino acid sequence as normal prion i.e.
  their primary structure is the same but their
  secondary structure is dominated by beta
  confirmation

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Abnormal Prions e.g. PrPsc

• Proteinacous Infectious Particle
• smaller than the smallest known virus
• self-replicating prions multiply by converting
  normal protein molecules into abnormal ones
  simply by changing their shape into that of the
  infectious protein molecules abnormal PrP is
  folded
• no genetic material/nucleic acids present as in
  the case of normal prions

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Abnormal Prions cont

• resists normal degradation techniques e.g.
  formaldehyde, ethylene oxide, temperature, UV
  light, proteases nucleases
• Stimulates no immune response in the host

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Protein-Only Theory

• hypothesis is based upon known properties of
  proteins with the added wrinkle that a protein
  molecule folded in an abnormal way can alter the
  folding of another protein molecule and thereby
  change its biological properties

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Replication Cycle of a Prion

• occurs when a normal PrPc protein is converted to
  PrPsc protein in the endosomal compartment of the
  cell, and is no longer recycled back to the
  surface of the cell
• when the PrPsc protein begins to accumulate in
  the endosomal compartments, amyloid deposits form
  and cause the cell (neuron) to loose viability,
  resulting in death
• Vacuolar change in grey matter spongiform 

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Conversion Sequence

• Change in structural configuration folding
• Formation of insoluble aggregates (amyloid
  plaques)
• Neuronal damage leading to neuronal death
• Death of the host
• Normal alpha helical configuration
• Abnormal beta pleated sheet configuration
  marker for infectivity

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New Form of Disease Transmission

• Until the 80s, scientists thought conveyors of
  transmissible diseases must include genetic
  material to infect a host however, in the case
  of the abnormal PrP this doesnt seem to apply

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TSEs Transmissible Spongiform Encephalopthies

• Scrapie sheep
• Chronic Wasting Disease elk deer
• Bovine Spongiform Encephalopathy
• Mink Transmissible Encephalopathy
• kuru, both classical and variant
  Creutzfeldt-Jakob disease (CJD),
  Gerstmann-Straussler-Scheinker syndrome, and
  fatal familial insomnia - humans
• Feline Transmissible Encephalopathy
• Abnormal/infective prions are species-specific

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Future Research Focus in Prion Research

• Alzheimer's disease and Parkinson's disease?
  Because suggestions that PrP protects the brain
  against dementia and other degenerative problems
  associated with old age prions may prevent the
  Purkinje cells from dying