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					PRIONS

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PRIONS
   Infectious agent made of proteins WHICH
    ARE NOT ASSOCIATED WITH A
    NUCLEIC ACID
   Infect by folding and unfolding into
    irregular conformations
   The abnormally folded molecule is able to
    convert proteins into correctly folded form
   This process perpetuates the infection
PRION DISEASES
   GENETIC COMPONENT
   INFECTIVE PARTICLE
   BOVINE SPONGIFORM
    ENCEPAHLOPATHY
HUMAN PRION DISEASES
   CREUTZFELD-JACOB DISEASE(   1 PER
    MILLION PEOPLE PER YEAR)
   FATAL FAMILIAL INSOMNIA
   KURU
   ALPERS SYBNDROME
MECHANISM
   All known prions are believed to
    infect and propagate by formation of
    an AMYLOID fold, in which the
    protein polymerizes into a fiber with
    a core consisting of tightly packed
    BETA SHEETS. Other mechanisms
    may exist in yet undiscovered
    infectious protein particles.
KURU – NEW GUINEA
CANNIBALISM
         Bovine Spongiform
          Encephalopathy (BSE), also
          known as "Mad Cow
BSE       disease," has emerged as
          one of the most serious
          health concerns of the 21st
          century.
         No one knows for certain
          what causes BSE or its
          human equivalent,
          Creutzfeldt Jakob disease
          (CJD). However, a majority
          of scientists suspect the
          culprit may be an aberrant
          protein known as a prion
          found in the brains and
          spinal tissue of infected
          animals.
         Experts also believe
          outbreaks of BSE in
          European cattle stem from
          the once common practice
          of feeding these animals
          OFFAL
AMYLOID PLAQUES IN
NERVOUS TISSUE
Holes produced by the
prions
    Prions - Genetics
   The prion is a product of a human gene, termed the PrP gene,
    found on chromosome 20.
   This gene contains two exons separated by a single intron.
    Exon I and Exon II are transcribed and the two RNAs
    ligated into a single mRNA. This mRNA contains an open
    reading frame (ORF) or protein coding region which is
    translated into the PrP protein.
   The PrP protein is a precursor of the prion protein. It is
    termed PrP 33-35.
The PrP 33-35 undergoes several post-translational
events to become the prion protein (PrP 27-30):


   1. Glycosylation - at two sites.
    2. Formation of a disulfide bond between two
    cysteine residues.
   3. Removal of the N-terminal signal peptide.
   4. Removal of the C-terminal hydrophobic
    segment.
   5. Addition of a phosphatidylinositol glycolipid at
    the C-terminal.
   6. Removal of the N-terminal first 57 amino
    acids.
Humans and infections
    Acquired infections
1.   Diet
2.   Surgery
3.   Corneal transplants
Hereditary factors
   A strain of mice that has a
    predisposition to prion related
    diseases
   Sporadic
   Appears to be a dominant pattern
Prion Genotypes
   Genetic predisposition for Scrapie in
    sheep
   Scrapie susceptible sequences have
    been located in sheep in New Zealand
    and Australia
Scrapie
FATAL FAMILIAL INSOMNIA;
FFI( OMIM) -
   Although the thalamus is affected in diffuse degenerative
    processes of the nervous system, a genetically determined
    degenerative disease limited to selected thalamic nuclei seems to
    have been described first by Lugaresi et al. (1986).
   They reported the case of a 53-year-old man who presented with
    progressive insomnia and dysautonomia (pyrexia, diaphoresis,
    myosis, and sphincter disturbances).
   Dreamlike status, dysarthria, tremor, and myoclonus subsequently
    developed and led to coma and death after 9 months. Two sisters
    of the patient and many relatives over 3 generations had died of a
    similar disease.
   Pathologic studies of the brains of the patient and 1 of his sisters
    showed severe neuronal degeneration, with reactive astrocytosis
    limited to the anterior and dorsomedial thalamic nuclei and without
    spongiosis or vascular or inflammatory changes.
Mice – Experimental
evidence
   Mice inoculated with brain homogenates from
    subjects with fatal familial insomnia or sporadic
    fatal insomnia had lesions of similar types and
    distributions in their brains.
   In both familial and sporadic fatal insomnia, the
    molecular mass of the Prp(Sc) fragment was 19 kD
    in these mice.
    In contrast, these characteristics were different
    in the mice inoculated with homogenate from
    patients with typical sporadic or familial
    Creutzfeldt-Jakob disease, and the molecular
    mass of their PrP(Sc) was 21 kD.

				
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posted:1/22/2012
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