Prions

Protein

1. PRIONS

2. In the 1950s, a district medical officer working in the highlands of New Guinea observed a fatal disease among the people of the Fore (FOR-ay) tribe. The Fore people called this sickness kuru , which means "trembling in fear." After intially becoming unable to walk, victims of kuru lost the ability to swallow or chew. Drastic weight loss would inevitably lead to death. Today we know that kuru is one of several diseases in humans and animals caused by prion (PREE-on) proteins. The Mystery of Kuru

3. Introduction to Prions Pronounced “ pree -on ” - Shortened term for: Proteinaceous Infections Particle - Causes TSE (Transmissible Spongiform Disease) which attacks the central nervous system (the brain).

4. Basic Structure Normal prions contain about 200-250 amino acids twisted into three telephone chord-like coils known as helices, with tails of more amino acids.

5. Basic Structure The mutated, and infectious, form is built from the same amino acids but take a different shape . 100 times smaller than the smallest known virus. Normal Mutated

6. Basic Structure Normal Mutated

7. Differences From Bacteria & Viruses Prions do not contain nucleic acid; they don’t have DNA or RNA . They are extremely resistant to heat and chemicals . Prions are very difficult to decompose biologically; they survive in soil for many years.

8. Prions (PREE- ons ) are proteins that are unique in their ability to reproduce on their own and become infectious. They can occur in two forms called PrP-sen and PrP -res.

9. Both PrP-sen and PrP -res are made up of the exact same string of amino acids, the building blocks that make up proteins. However, the two forms have different shapes. PrP-sen is produced by normal healthy cells. The sen stands for “sensitive” because this version of the protein is sensitive to being broken down. PrP-sen is present mainly in neurons in the brain, but is also found in other cell types.

10. Scientists don’t know the exact function of PrP-sen , but there is evidence that it may be involved in communication between neurons, cell death, and controlling sleep patterns. Interestingly, mice that are genetically engineered to produce no PrP-sen seem to be healthy. The second type of prion protein, known as PrP -res, is the disease-causing form. Organisms with it develop spongiform disease. “res” stands for “resistant” because this version of PrP is resistant to being broken down.

11. Unlike other infectious agents, prions do not contain genetic material. However, once they infect an individual, prions can replicate. How is this possible? Scientists are still working out the details, but evidence supports the idea that when PrP-sen comes into contact with PrP -res it is converted to PrP -res. The result is a chain reaction that multiplies copy after copy of the infectious prion . Because of their abnormal shape, PrP -res proteins tend to stick to each other. Over time, the PrP -res molecules stack up to form long chains called “ amyloid fibers”.

12. Amyloid fibers are toxic to cells, and ultimately kill them. Cells called astrocytes crawl through the brain digesting the dead neurons, leaving holes where neurons used to be. The amyloid fibers remain.

13. The History of Prions : 1730s Earliest written record of Scrapie in English sheep; already prevalent in central Europe.

14. 1950s High levels of kuru appear among the Fore people of New Guinea. 1960s Scientists experimentally transmit Kuru and CJD to chimpanzees, demonstrating the transmissible nature of these diseases.

15. 1980s 60 people die from CJD after being infected by contaminated surgical instruments. 85 people die after receiving prion -infected growth hormone injections.

16. 1982 Dr. Stanley Prusiner coins the term " prion " ( PROteinaceous INfectious particle). Highly purified PrP -res is shown to be infectious. He goes on to win the Nobel Prize in Medicine in 1997.

17. 1985 Scientists identify the PrP gene and discover that uninfected people produce a normal form of the PrP protein.

18. 1986 By the year 2000, nearly 180,000 cattle will become infected. To stop the spread, thousands of cattle are killed.

19. A Survey of Spongiform Diseases

20. Classic CJD or Creutzfeldt-Jakob disease (human) The most prevalent of the spongiform diseases Occurs spontaneously in 1 out of a million people 10% of cases are inherited mutations in the PRPN gene Usually strikes people age 50 to 75 Symptoms: dementia, muscle twitching, vision problems Fatal Familial Insomnia (human) All cases are inherited mutations in the PrP gene Usually strikes people age 36 to 61 Disruption of sleep/wake cycle leads to coma, then death Scrapie (goats, sheep) Occurs as infection in genetically susceptible sheep There is no evidence of spread to humans

21. BSE or Bovine Spongiform Encephalopathy (cattle) Also known as "Mad Cow Disease" because infected animals act strangely and can be aggressive Spread rapidly through Britain by rendering Chronic Wasting Disease (deer, elk) Infectious disease in wild deer and elk primarily in the western United States Drooling, difficulty swallowing, weight loss Kuru (human) Struck members of the Fore tribe in the 1950s and 1960s Muscle weakness, loss of coordination, tremors, inappropriate episodes of laughter or crying Transmitted by ritual cannibalism as part of funeral ceremonies

22. Controversy DNA and RNA are the only substances now known to replicate in body tissues, so how do prions make copies of themselves without any nucleic acids? Some believe TSEs are caused by an unidentified slow-acting virus. Others believe a small virus accompanies a prion and they work together to cause disease.