2. Creutzfeldt-Jakob disease (CJD) is a rare, fatal, brain disorder. It
affects about one person in every one million per year worldwide. CJD
usually appears later in life and runs a rapid course. Typically,
symptoms will begin to occur at the age 60, and 90 percent of
individuals with this disease will die within 1 year. Early stages of this
disease, people may experience failing memory, behavioral changes,
and lack of coordination.
3. CJD belongs to a family of human diseases known as the transmissible
spongiform encephalopathies (TSEs). Spongiform refers to the characteristic
appearance of the infected brains, which become filled with holes until they
resemble sponges under a microscope.
Some researchers believed an unusual "slow virus" or another organism caused
CJD. However, they have never been able to isolate a virus or prove this
hypothesis. Furthermore, the mediator that causes CJD has several
characteristics that are unusual for known organisms. It was difficult to kill, it
did not appear to contain any genetic information in the form of nucleic acids
(DNA or RNA), and it usually had a long incubation period before symptoms
appear. In some cases, the incubation period may be as long as 50 years. The
scientific theory at this time describes that CJD and the other TSEs are caused
by a type of protein called a prion.
4. What is a Prion?
The term prion is derived from a protein infectious particle, and
refers to the pathogen that causes transmissible spongiform
encephalopathies (TSEs).
This small infectious particle is a disease-causing form of a protein
called cellular prion protein (PrPc). PrPc is mainly found on the
surface of cells in the central nervous system, but can also be located
in other bodily tissues.
5. How are Prions formed?
Post-translational modifications are the modifications of proteins during and
after protein synthesis. This mutation occurs at this time during the N-
glycosylation. During this time, the N-terminal site of the protein is misfolded
and one of these cleavages are found within the GPI anchor. There is a
cleavage at this site, therefore, causing a polypeptide chain to be released
into the extracellular medium. And this caused the GPI anchors to be
physically inaccessible to the phospholipases.
6. Question: How are the GPI anchors in
PrPc different from other organisms?
A. They contain more mannose residues than normal
B. Their cores are modified by an addition of sialic acid residue
C. The core structure doesn’t include an ethanolamine residue
D. The GPI anchor is found in the mitochondria instead of the ER.
Answer: B
7. This is an example of a protein misfolding that causes different diseases
such as CJD. As shown:
8. How does the misfolding affect the
protein?
As seen the picture, the beta sheets are generally affected.
The assumption is that amyloid-like fibrils are formed by two tightly binded β-
sheets in a zipper-like manner. This allows for nucleation to fibril forming to
occur. This process can also start by the unveiling of short zipper-forming
segments, which then stack into β-sheets.
the β-sheets fold into β-helices. Three of these β-helix molecules form the
basic unit for a PrP fibril.
9. Question: What is the “Octapeptide
repeat” in PrP?
A. It is a nonsense mutation that changes an amino acid in the Octapeptide
sequence but forms the same protein
B. It is the deletion of copies of an octapeptide in the protein.
C. Nothing changes, but the protein contains 5 copies of the Octapeptide.
D. It is an insertional mutation, where 1-9 additional copies of an Octapeptide
is added.
Answer: D
10. What is the function of these
Octapeptide repeats?
These repeats serve as a pH-dependent folding site.
If this site is affected by the extra copies this could cause the protein to
misfold and cause it to create a infectious copy.
11. References:
"Creutzfeldt-Jakob Disease Fact Sheet." National Institutes of Health. U.S.
Department of Health and Human Services, n.d. Web. 16 Dec. 2016.
Kupfer, L., W. Hinrichs, and M.H Groschup. "Prion Protein Misfolding." Current
Molecular Medicine. Bentham Science Publishers Ltd., 2009. Web. 16 Dec.
2016.
