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Title: 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


1
Fatal Familial Insomnia Pathogenesis caused by a
mutation affecting the metabolism of the normal
prion protein.By Sabrina T. GilligBIO-475
SeminarDr. Peter Lin
2
FATAL FAMILIAL INSOMNIAthe nightmare of those
who never sleep
  • Dateline NBC. 2005. Fatal Insomnia Genetic
    mutation inflicts rare disease through
    generations. http//www.msnbc.msn.com/id/6822468/
    . Accessed 11 APR 2006. CLICK ON THE LINK TO
    WATCH THE VIDEO !

3
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.
4
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.

5
Prion diseases (Collinge, 2005)
6
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 (N)
    for aspartic acid (D)? D178N
  • 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.

7
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.
  • Sponge-like appearance under the microscope-TSE-

8
Treatment
  • There is no treatment for FFI.
  • Two drugs (quinacrine and chlorpromazine) were
    being tested, but the individuals in the clinical
    trials worsened.

9
Based on
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.
10
Metabolism of the mutated prion protein
  • Codon 129 Polymorphism
  • PRNP encodes for methionine or valine.
  • CJD and FFI similarities
  • The normal haplotype is designated 178D, the
    haplotype in FFI is designated D178N.

11
  • The metabolic and mutational events that lead to
    the syndrome will be examined further along this
    presentation.

12
Expression, Localization and metabolism of the
PrP in humans
  • PrPc is a glycoprotein attached to the cell
    membrane .
  • During the process of translocation in the ER,
    PrPc continues its folding process.
  • Further folding occurs in the Golgi apparatus

13
N-Linked Glycosylation
  • Is common to all eukaryotic cells. It is
    imperative for proper folding of the protein.

14
The secretory Pathway ( Schuldiner et al., 2005)
15
Schematic Representation of The Prion Protein
-The human PrP. Polymorphic sites 129 and 178 are
shown. GPI (ground positioning indicator) anchors
the prion protein to the cell membrane.
16
Three forms of PrPc
  • Called GLYCOFORMS and differ in the level of
    glycosylation (addition of sugar units).
  • 1) Unglycosylated
  • 2)monoglycosylated
  • 3)diglycosylated

17
Cell lines and their different genotypes
18
Glycosylation differences among mutant and normal
cells on the cell surface
  • The cells were treated with PI-PCL.
  • Scientists were able to study the prion protein
    itself and quantify solely the amount of PrP
    present on the cell surface.

M mature I Intermediate U Unglycosylated
19
Results
  • 3 different glycoforms were observed
  • Only 1/3 the amount of PrPm was released from the
    cell surface of mutant cells when compared to the
    control.

20
Glycosylation differences on the cell
surface-Normal vs. Mutant-
  • Enzyme N-Glycosidase F was used to remove the
    sugar groups.

21
Results
  • The unglycosylated form is underrepresented on
    the cell surface.

22
Efficiency of the PI-PCL on the mutant PrP
  • To prove that the mutant prion protein is
    efficiently unanchored by the PI-PCL treated (),
    and untreated (-) cells were labeled with biotin.
    As seen in this figure, PrPm is powerfully cut
    by PI-PCL treatment

23
Scientists concluded that
  • The three PrP forms differ in the level of
    glycosylation? In mutant cells the unglycosylated
    form is virtually inexistent.

24
Prion Protein representation inside the cell and
on the cell surface
  • Scientists had to quantitate the amount of PrP
    present inside and on the cell surface.
  • INTRACELLULARLY
  • Retention of the prion protein
  • EXTRACELLULARLY
  • Amount present on the cell surface

25
Graphical Representation of unglycosylated PrP
intracellularly and on the cell surface.
26
What does this mean?
  • INTRACELLULARLY At zero time PrP is still in the
    ER-Golgi complex
  • EXTRACELLULARLY The mutant PrP is inadequately
    transported during the secretory pathway

27
How does the stability of PrPm affects its
transport to the cell surface?
  • Glycosylation was prevented using the antibiotic
    tunicamycin.
  • -Tunicamycin treated ()
  • Untreated (-)

28
Cells treated with Tunicamycin
29
Results
  • 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.

30
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).

31
Effects of transport block in the degradation of
the PrP
  • Scientists wanted to find out where the PrPm is
    digested.
  • The PrPc showed no major changes with time
  • PrPm amounts decreased

32
Results
  • 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.

33
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.

34
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.

35
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.

36
Presence of unglycosylated PrP in the brain of
FFI patients
  • Scientists examined the PrPm present in a FFI
    patient, in a section of the brain which does not
    have PrPres. All N-linked sugars in the FFI
    patient sample were removed by the enzyme PNGase,
    to study the original glycoforms.

37
Results
  • In the mutant gray matter the unglycosylated form
    is present at only about 1/3 when compared to the
    normal samples.

38
What appears to be the cause of disease in FFI?
  • FFI appears to result only from the degradation
    of the unglycosylated form before it reaches the
    cell surface.

39
Conclusion
  • 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 1990s).

40
Conclusion
  • Even though FFI and other prion diseases are rare
    and sporadic, science should always try to stay a
    step aheadfor the sake of all humanity.

41
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