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BRAIN EATER
Bradford High School SMART Team: Maria Barnes, Mahmood Cheema, Tony Clark, Michelle
Goettge, David Jensen, Fred Seewald, Steve Snowden, Beth Stebbins, Josh Swenson
Advisor: Mrs. Jean Lee
Mentor: Anita L. Manogaran, PhD., University of Illinois at Chicago
ABSTRACT
Many proteins are misfolded and dysfunctional when first
formed. Chaperone proteins are used to refold, protect and
disaggregate misshapen proteins. While chaperones are
traditionally beneficial, it has been recently found they play a role
in the formation of infectious protein aggregates. These
infectious proteins are called prions and the diseases they cause
have no known cure. Prions are responsible for transforming
healthy brain proteins into prion replicas, therefore spreading the
disease and disrupting normal functions. This transformation
occurs when the mainly alpha helical form of the PrPc protein
changes into a beta sheets rich protein. This conformational
change can cause a variety of neurodegenerative diseases,
such as Mad Cow Disease in cattle, Scrapie in sheep and
Creutzfeldt-Jacobs Disease in humans. Prions are found not
only in mammals, but in other organisms as well, and have been
extensively studied in yeast. One prion in yeast is called
[RNQ+], which is the misfolded aggregate form of the Rnq1
protein. The chaperone protein Sis1 binds to the Ssa1
chaperone and seems to influence formation of the prion.
Chaperones break the protein aggregate into smaller pieces that
can be passed on to many daughter cells. Because the pieces
have more sticky ends than the original aggregate, they can
attract more normal protein and convert them to the prion form.
Scientists hope to explore the structure of Sis1 and its peptide
binding fragment to further understand how prions work.
What is prion disease?
A family of infectious diseases that affect the
brain. These diseases include Mad Cow in
Cattle, Scrapie in Sheep, and CreutzfeldtJacob’s disease in Humans.
Some symptoms of prion diseases include:
depression, lack of coordination, muscle
spasms, insomnia, confusion, memory
problems, and paralysis.
A
Cross-section of brain
tissue from patients with
Creutzfeldt-Jacob’s
disease. Diseased brains
show extensive spongelike legions (bottom
panel) compared to
healthy individuals (top
panel).
What is the cause of prion disease?
A prion is caused by a misfolded protein. "Prion" is short for
"proteinaceous infectious particle." Prions, can transform
healthy brain proteins into prion replicas, disrupting the
normal functioning of brain cells.
MECHANICS
Chaperones
Most proteins are misfolded and dysfunctional
when first formed. Chaperones are used to refold,
protect, and disaggregate misshapen proteins.
Nonfunctional,
Misfolded
Protein
Healthy proteins (red squares) can
misfold in a stable conformation (green
triangle). The misfolded protein converts
the normal protein into the prion form, and
can cause further aggregation of the
healthy protein (clump of green triangles).
Study of prions in yeast
Prions have been extensively studied in yeast. The study of
yeast prions has proven that prions are caused by proteins,
and has provided a greater understanding of how prions work.
One prion in yeast is called [RNQ+], the misfolded form of the
Rnq1 protein.
Rnq1
Prions
Functional
Protein
Chaperone
Chaperones are believed to play a major role in
the formation of prions. The Sis1 chaperone
binds to the Ssa1 protein, and is thought to
allow the heat shock protein 104 (HSP 104) to
break the prion aggregate into smaller pieces.
This then allows the smaller prion pieces to be
transferred into daughter cells later on during
mitosis.
Prion aggregate
GFP
SIS1 SSA1
+
When the Rnq1 protein is fused to a Green Fluorescent Protein
(GFP), the protein shows diffuse fluorescence in normal cells
(panel A) and localizes into distinct aggregates in prion containing
cells (panel B).
A
B
Aguzzi, A., Montrasio, F., and Kaeser, PS. (2001). Prions: health scare and
biological challenge. Nature Reviews Molecular Cell Biology. 2, 118-126.
A SMART Team project supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)
hsp104
In Summary
Much is still unknown about prions and the
exact interactions between prions and
chaperones. Ongoing research is attempting to
explain in detail the interaction of Sis 1, Ssa 1,
HSP104, and prion aggregates; as well as the
ability of prions to maintain a stable, infectious
conformation.