Transcript Fatal Familial Insomnia - UNM Biology Department Home Page

Prions
Alicia Arguelles, Jerry Wang
May 4, 2007
What are prions?
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proteinaceous infectious particle
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The PRNP gene encodes for the prion
protein (PrP)
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an infectious agent made only of protein,
containing no nucleic acids
PrP is active in the brain and several other
tissues
The normal form of the protein is called PrPC,
while the infectious form is called PrpSc
General information
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Prions are believed to infect and multiply by
refolding abnormally into a structure that is able to
convert normal protein into an abnormal form.
Prions are quite resistant to denaturation by
protease, heat, and radiation, almost nothing kills
them!
In order to be denatured they must be autoclaved
at 134 degrees Celsius for 18min.
Although, prions have a genetic component, it is
also know that they can be transmissible via
spongiform encephalopathies.
Different types of prion
diseases
scrapie (a disease of sheep)
 chronic wasting disease (in deer and elk)
 bovine spongiform encephalopathy (BSE or
mad cow disease)
 Gerstmann-Strausler-Scheinker syndrome
(GSS)
 Creutzfeldt-Jacob disease (CJD)
 Fatal Familial Insomnia (FFI)
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Characteristics of prion diseases
Also known as TSE (transmissible
spongiform encephalopathy)
 Affects brain or other neural tissue
 Untreatable and fatal
 Phenotypic variability
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Hereditary (10-15%), transmissible, sporadic
Prions and the brain
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Kuru and vCJD are
known to be
transmitted to humans
who have eaten the
meat or brains of
infected animals or, in
the case of Kuru,
infected humans.
(Yummy anyone for
some brain?)
How Prions Access the Brain..
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How can prions, which are
merely proteins, make their way
through the gut and into the
brain, where they cause the
scary spongiform encephalitis?
We all know that proteins
normally are digested down to
amino acids in the gut, and
transported through the gut
epithelium by amino acid
transporters. Well if Prions took
this route they would not longer
be infectious, so…
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We already know that Prions are
extremely resistant to
degradation so they are not
broken down and digested.
Even so, they should not be
absorbed across the intestinal
wall, right?
In fact, they circumvent the
normal process of intestinal
absorption by passing into the
Gut-Associated Lymphoid Tissue
(GALT). Related to this, it seems
that chronic inflammation
predisposes to prion infectivity,
e.g. in rheumatoid arthritis, type-I
diabetes, or Crohn’s disease.
How Prions Access the Brain
Cont..
It is believed that the immune system plays a
big role in neuroinvasion.
 Follicular Dendritic Cells (FDCs) being that
they are mobile could function as the bridge
between the GI tract and the lymphoid
organs, where the prions can replicate.
 The process by which prions are transported
is not fully understood, further research is
needed.
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Proposed mechanism of prion
propagation
Molecular model of PrPc and PrPSc
structures Protein refolds abnormally
Normal
Diseased
Bovine spongiform encephalopathy
(BSE) mad cow disease
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This is a fatal
neurodegenerative
disease of cattle
An epidemic in Brittish
cattle occurred when
farmers started to use
animal by-product as
the main source of feed
for their cattle.
This lead to an over all
higher rate of infection
and disease.
Deaths From BSE
In the early 1900s a new variant of
Creutzfeldt-Jakob disease (vCJD) was
discovered and linked to BSE
 This disease in 2004 had killed 157 people in
Europe.
 148 cases occurred in the United Kingdom, 6
in France, and 1 in Italy.
 In the US there have only been 3 vCJD
cases reported to date.
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Classic Creutzfeldt-Jakob disease vs. CreutzfeldtJakob disease (vCJD)
Characteristic
Classic CJD
Variant CJD
Median age of death
68 years
28 years
Median duration of illness
4-5 months
13-14 months
Clinical signs and
symptoms
Dementia; early
neurological signs
Prominent
psychiatric/behavioral
symptoms; painful
dysesthesias; delayed
neurological signs
Cases of BSE
Summary
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Prions are toxic because they are not denatured
easily and can accumulate in the body.
Prions can be ingested via taunted meat and
maybe transported by the immune system to the
brain where they cause damage. (scientists still are
not certain who they get transported)
Moral of the story feeding cows animal by-products
to save money is not safe for humans.
Sources
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Center for Disease Control and Prevention, vCJD (Variant Creutzfeldt-Jakob Disease)
http://www.cdc.gov/ncidod/dvrd/vcjd/factsheet_nvcjd.htm#cjdvsnvcjd
Chakraborty, C. et al. Prion Disease: A Deadly Disease for Protein Misfolding. Current
Pharmaceutical Biotechnology 2005. 6: 167-177
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Gambetti, P. et al. Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia.
Clinics in Laboratory Medicine 2003. 23: 43-64
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Mead, Simon. Prion Disease Genetics. European Journal of Human Genetics 2006. 14:
273-281
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Genetics Home Reference. PRNP. National Library of Medicine. November 20, 2006.
http://ghr.nlm.nih.gov/gene=prnp;jsessionid=14FA35F8A6BD29FEE4F0BDD3A29217
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Pearson, George. Oregon State. Prions.
http://oregonstate.edu/instruction/bb492/lectures/Prion.html
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Wikipedia Free Encyclopedia, Creutzfeldt-Jakob disease
http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease