Beyond Viruses…Beyond Viroids… Can create an “infection” that can lead to the death of the “infected organism? …appears to be able to replicate itself… …is not a bacteria! …is smaller than a virus? …is not a virus! …contains no genetic information …whose structure is made by all living things…

PROteinaceous INfectious particle. PRIONS: The Brain Eater… A PRION is a… PROteinaceous INfectious particle. This simply means that a protein can cause a particular disease and it can be given to another individual and they can then get the same disease. HYPOTHESIS

PRIONS: DID YOU KNOW… People often assume that scientists try to prove hypotheses or theories. WRONG Hypotheses can never be proved; they can only be disproved. A hypothesis that fails one or more tests is considered disproved and it is discarded. A valid hypothesis can be revised.

PRIONS: The Brain Eater… In Class Reading… The History of Scrapie, CDJ and Kuru

PRIONS: Are PRIONs a new form of life? 1- Are PRIONs made of cell? NO 2- Are PRIONs organized? YES 3- Do PRIONs use energy? 4- Are PRIONs responsive? NO (hypothesized)

PRIONS: Are PRIONs a new form of life? 5- Do PRIONs grow? (enlarge and divide) NO 6- Do PRIONs reproduce? YES (hypothesized) ~kind of, they recruit normal proteins by changing their shape 7- Do PRIONs adapt? Don’t know yet, they may mutate in other viable forms however.

PRIONS: Are PRIONs a new form of life? 8- Do PRIONs die? NO, however like all proteins, their structure can be degraded or denatured by heat. 9- Do PRIONs come from pre-existing prions? YES (hypothesized) ~ existing PRIONs convert normal Prion-like protein structures into abnormal viable PRION geometries.

PRIONS: Origin & Structure Pre-infectious prion proteins or PrPc, like this one are naturally created by and are found in the membranes of normal host cells. Image http://www.bio.vu.nl/thb/users/ingeborg/p1.gif FACT

PRIONS: Origin & Structure FACT All mammals appear to have prion protein genes and the gene sequences are similar, but not identical, in related species. Image http://www.mad-cow.org/~tom/helix_anim.html

PRIONS: Transformations Image http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_p1.html

PRIONS: Transformations Image http://www.mad-cow.org/~tom/helix_anim.html

HYPOTHESIS PRIONS: Infection O – Origin of PRIONs Contaminated meat Digestive Track Blood Stream L – White Blood Cell S – Spleen N – Spleen to Brain B – Brain HYPOTHESIS Image http://www.rkm.com.au/BSE/prionsprogress.html This very simplified diagram shows the likely routes of BSE prions from their amplification through cows to their entry to the human brain. The prions are represented by the purple particles streaming around the picture. At top left "O" represents the origin of BSE prions. This has not been established with certainty. The prions are then shown passing from one cow to another (BSE infected cattle were fed to other cows). Contaminated meat (and possibly other bovine derivatives) then carried the prions to humans. In the human gut (bottom left) prions may be taken up by lymphoid tissues (Peyer's patches). The prions are then ferried around the body in lymphocytes "L". Prion replication is thought to occur in lymphoid tissues, especially the spleen "S". Nerves "N" that supply the lymphoid tissues then allow prions to travel back up them to the brain. Since lymphocytes carry prions, it is reasonable to assume that transport to the brain might occur in parallel through the blood. This is illustrated at "B". The fear that human blood and blood products may carry BSE prions has caused many countries to ban blood donations from those who are deemed to have been exposed. It must be emphasised that prion biology is not fully understood and much remains speculative. This picture is an attempt to illustrate various concepts but nothing is intended to be definitive. The picture was painted digitally and so it can be easily modified as and when mechanisms are elucidated.

HYPOTHESIS Rouge Infectious PRION > PRIONS: Transformation Normal Protein HYPOTHESIS Nerve Cell Rouge PRION Transforms Normal Prion Prions are pathogenic variants of proteins that are naturally produced in nerve cells and certain other cells. The normal "healthy" prions are referred to as PrPc (Prion Protein cellular). The word "prion" stands for "proteinaceous infectious particle" and so should properly only be applied to the pathogenic variants. In this picture, the production of PrPc is illustrated from the nucleus at bottom right. RNA that codes for PrPc is produced in the nucleus and exits via the nuclear pore. The RNA then passes along ribosomes attached to the rER. PrPc is formed in the rER and then progresses up through the Golgi. At the upper face of the Golgi, vesicles containing PrPc bud off and travel to the cell surface. Here, they fuse with the cell membrane and so discharge their cargo at "PrPc". By this means, the cellular proteins come to sit on the exterior of the cell. At "f", PrPc encounter rogue (purple) prions. These are termed PrPsc (sc stands for scrapie, the prion disease of sheep). The rogue prions seem to force the normal proteins to change shape. Both types of protein, the PrPc and their corresponding prions, are the same chemical - just different shapes. It is this shape-flipping which is equivalent to the transmission of infection. Such a conformational shift or flip could happen at the cell surface or in caveolae (one is shown as a small invagination in the cell membrane). Residual PrPc might continue to be flipped by contact with the rogue confomations for some time in these vesicles. Prions polymerise, finally appearing as purple fibrils in the picture at "P". PrPsc is resistant to degradation by the enzymes contained in the lysosomes that are seen floating nearby. Consequently, PrPsc accumulates in the cell. PrPsc vesicles may also travel to the Golgi and intercept PrPc that is being processed there. In this way, PrPc particles could be switched to the rogue form before they reach the surface of the cell. By such mechanisms, PrPc might be switched to PrPsc at various points in and on the cell. Prions could enter the brain along the axons of neurons, shown here at "ax". This probably happens by a retrograde flow of prion filled vesicles. These are shown in the picture as purple spheres ascending the axon like elevators going up a shaft . Another route of entry could be the blood, probably in immune cells. A lymphocyte "im" is shown exiting the capillary at bottom left where it could then contact the astrocyte "ast". Astrocytes and other glial cells also support the production of prions. It must be emphasised that prion biology is not fully understood and much remains speculative. This picture is an attempt to illustrate various concepts but nothing is intended to be definitive. The picture was painted digitally and so it can be easily modified as and when mechanisms are elucidated. The original is 3,548 pixels across and shows things in much greater detail than is seen on this web page. It is available worldwide for licensing. If you have any comments, please let me know. Image http://www.rkm.com.au/BSE/

“Shape Shifting” Normal Prions Infectious PRIONS PRIONS: Shape Transformation “Shape Shifting” Normal Prions Infectious PRIONS Before Images http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_h1.html http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_s1.html AFTER

Normal Prions Infectious PRIONS PRIONS: Shape Transformation Before AFTER Images http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_h1.html http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_s1.html Normal Prions Infectious PRIONS

PRIONS: What is the evidence? Normal Brain Tissue “Dead Space” AFTER Before Images http://www.bio.vu.nl/thb/users/ingeborg/PrionImages_h1.html Amyloid deposition in tissue is a pathological manifestation of many diseases, of both prion and non-prion etiology. These diseases include Alzheimer's disease, *Creutzfeldt-Jakob disease, Down's syndrome (mongolism), *fatal familial insomnia, *Gerstmann-Straussler syndrome, *kuru and leprosy. (* indicates prion diseases). Amyloid Clusters Diseased Brain Tissue

PRIONS: What is the Impact? One part of the prion protein can cause apoptosis, or programmed cell death; FACT …perhaps this mechanism explains the pattern of the disease. HYPOTHESIS

PRIONS: What is the Impact? Prions induce no immune reactions within the human. FACT …perhaps this mechanism explains the pattern of the disease. HYPOTHESIS