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PRIONS. 221. 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.

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Prions

PRIONS

221


Prions1
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
PRION DISEASES

  • GENETIC COMPONENT

  • INFECTIVE PARTICLE

  • BOVINE SPONGIFORM ENCEPAHLOPATHY


Human prion diseases
HUMAN PRION DISEASES

  • CREUTZFELD-JACOB DISEASE( 1 PER MILLION PEOPLE PER YEAR)

  • FATAL FAMILIAL INSOMNIA

  • KURU

  • ALPERS SYBNDROME


Mechanism
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.




BSE

  • Bovine Spongiform Encephalopathy (BSE), also known as "Mad Cow 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




Prions genetics
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
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
Humans and infections become the prion protein (PrP 27-30):

  • Acquired infections

  • Diet

  • Surgery

  • Corneal transplants


Hereditary factors
Hereditary factors become the prion protein (PrP 27-30):

  • A strain of mice that has a predisposition to prion related diseases

  • Sporadic

  • Appears to be a dominant pattern


Prion genotypes
Prion Genotypes become the prion protein (PrP 27-30):

  • Genetic predisposition for Scrapie in sheep

  • Scrapie susceptible sequences have been located in sheep in New Zealand and Australia


Scrapie
Scrapie become the prion protein (PrP 27-30):


Fatal familial insomnia ffi omim
FATAL FAMILIAL INSOMNIA; FFI( OMIM) - become the prion protein (PrP 27-30):

  • 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 – Experimental evidence become the prion protein (PrP 27-30):

  • 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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