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Fatal Familial Insomnia: Pathogenesis caused by a mutation affecting the metabolism of the normal prion protein. By Sabrina T. Gillig BIO-475 Seminar Dr. Peter Lin.

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Fatal Familial Insomnia: Pathogenesis caused by a mutation affecting the metabolism of the normal prion protein.By Sabrina T. GilligBIO-475 SeminarDr. Peter Lin


Petersen, R.B., P. Parchi, S.L. Richardson, C.B. Urig, and P. Gambetti. 1996. Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. The Journal of Biological Chemistry 271: 12661-12668.

what are prions
What are Prions?
  • Prions are the smallest infectious particles known to date. They are made only of a protein.
  • Prions are abnormally folded proteins.
  • Prions are the cause of transmissible spongiform encephalopathies.
  • Prion diseases are fatal and untreatable.

Cann, 1997.

more on prions
More on prions
  • The normal prion protein PrPc is found primarily on the surface of neurons, and is likely to be a synaptic protein with functional role in the synaptic transmission.
  • Prion diseases exhibit an extended latency period, spending this time performing neuroinvasion.
what is fatal familial insomnia
What is Fatal Familial Insomnia?
  • FFI is an autosomal dominant inherited disease; cause by a mutation of the normal prion protein.
  • A mutation in codon 178 replaces asparagine for aspartic acid.
  • First symptoms to arise trouble sleeping, difficulty concentrating , and personality changes
  • These symptoms usually appear during midlife, after appearance of the first symptoms death follows usually with 18 months.
the thalamus wikipedia 2006
The Thalamus (Wikipedia, 2006)
  • The thalamus is the point where most signals from the CNS pass to the cerebrum.
  • Severe loss of neurons in the thalamic nuclei, and accumulation of amyloid plaques.
  • When brain tissue is examined under the microscope, numerous tiny holes are visible, giving it a sponge-like appearance- From these observation the name TSE arose.
  • There is no treatment for FFI.
  • Two drugs (quinacrine and chlorpromazine) were being tested, but the individuals in the clinical trials worsened.
metabolism of the mutated prion protein
Metabolism of the mutated prion protein
  • The polymorphism in codon 129 is exclusive to humans. The two common forms of PRPN are the major determinants in the phenotypic expression of TSEs.
  • PRNP encodes for methionine (sulfur-containing aminoacid) or valine (essential aminoacid for growth).
  • CJD and FFI both present a mutation in codon 178, but codon 129 is the one that determines the phenotype.
  • The normal non-mutant haplotype is designated 178D, the haplotype in FFI is designated D178N.
  • The metabolic and mutational events that lead to the syndrome will be examined further along this presentation.
expression localization and metabolism of the prp in humans
Expression, Localization and metabolism of the PrP in humans
  • PrPc is a glycoprotein attached to the cell membrane .
  • During the process of translocation (rearrangement occurring when a piece of one chromosome is broken off and joined to another chromosome ) in the ER PrPc continues its folding process.
  • Further folding occurs in the Golgi apparatus
three forms of prp c
Three forms of PrPc
  • Called GLYCOFORMS and differ in the level of glycosylation (addition of sugar units).
  • 1) Unglycosylated
  • 2)monoglycosylated
  • 3)diglycosylated
purpose comparison among normal and mutant cells in the metabolism of the prion protein
-Purpose-Comparison among normal and mutant cells in the metabolism of the prion protein
  • Cells from the FFI haplotype only released 1/3 the amount of PrP to the cell surface when compared to normal cells.
  • Confirms that the three PrP forms differ in the level of glycosylation→ In mutant cells the unglycosylated form is virtually inexistent.
transport in the secretory pathway
Transport in the secretory pathway
  • Distinct amounts of glycosylation in normal and mutant forms indicate that the mutant PrP is not adequately transported during the secretory pathway.
stability and transport of the prion protein
Stability and transport of the prion protein
  • Experimental

By using the antibiotic tunicamycin (which prevents glycosylation in newly synthesized proteins), effect of the glycosylation in the transport of the PrPm was evaluated.

  • The unglycosylated form of the D178N PrPm

is degraded inside the cell, while the normal PrPc necessitates glycosylation to reach the cell surface.

  • When glycosylation is prevented, the PrPm hardly arrives to the cell surface, and untraceable after synthesis.
prp degradation
PrP Degradation
  • Experimental

In order to find out whether PrPm is degraded when kept in the ER-Golgi compartment scientists used brefeldin A (which blocks transport of glycosylated proteins from the ER to the Golgi complex).

  • Normal cells + Brefeldin A

All three glycoforms were observed

  • Mutant cells + Brefeldin A

Mutant cells exhibited degradation or change to the glycosylated form

→More unglycosylated PrPm reaches the cell surface when valine is present in codon 129.

results continued
Results (continued)
  • Degradation of the mutant prion protein does not occur in the Golgi compartment, but in the endosomal-lysosomal system, which contains highly acidic enzymes.
d178n mutant cells lack prp res
D178N mutant cells lack PrPres
  • Normal and mutant cells were tested for proteinase K-resistant PrP.
  • Mutant cells lack PrPres which provides resistance to powerful denaturing conditions.
underrepresentation in the brain of the prp m
Underrepresentation in the brain of the PrPm
  • Western Blot was used to determine whether the unglycosylated form of the mutant prion protein is decreased in FFI patients.
  • Portions of normal and diseased brain were examined.
  • Normal gray matter presented the three previously discussed glycoforms which transfer as a single unit after deglycosylation.
  • In the mutant gray matter the unglycosylated form is present at only about 1/3 when compared to the normal samples.
  • Pathogenesis in FFI and other prion diseases is believed to be caused by a change in the shape of the normal protein.
  • It is imperative to continue research, since in other neurodegenerative diseases (e.g. Alzheimer's) a misfolded protein could also be the cause.
  • A detailed analysis of the different factors, mechanisms and disease expression may be critical in the even of an epidemic (Mad Cow disease in the mid 1990’s).
  • Even though FFI and other prion diseases are rare and sporadic, science should always try to stay a step ahead…for the sake of all humanity.
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