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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.