Prions

There are different types of prion diseases that affect people. What are two general ways that these prion diseases differ from each other?

Different prion diseases have different symptoms and PrPRes pattern formations that is likely due to the different ways that PrP misfolds

What does the term "prion" stand for?

Proteinaceous Infection - protein that can cause infectious disease

14) True or False. Suppose that Person X and Person Y both eat the same amount of prion-infected meat. Both people have an equal chance of coming down with prion disease.

False

True or False. It is possible for a person to get prion disease by eating beef (cow meat) that contains PrPRes.

False

True or False. The more PrPRes aggregates you see in an animal's brain, the more severe the prion disease in that animal.

False. The amount of PrPRes in the brain doesn't indicate how severe the prion disease is. Some animals may have really severe prion disease but not as much PrPRes aggregates as compared to a brain with more PrPRes aggregates but have a milder version of the disease. It is not the PrPRes aggregates itself that cause the neurological problems but it's thought that there's an intermediate from PrPC to PrPRes that's actually causing toxicity to the brain

15) Scientists still have many unanswered questions regarding prion disease. What are three of these questions?

How/why PrPRes causes PrPC to misfold How PrPRes crosses blood-brain barrier How PrPRes enters each individual brain cell

19) Is there any evidence to suggest that something other than PrPRes is required to transmit prion disease? Explain your answer.

Just having the misfolded protein touch the healthy PrPC protein touch is not enough. It has to be the misfolded protein plus something else that you find in the brain in order for the PrPC to become misfolded.

Name two examples of prion diseases in humans.

Kuru (first prion disease described that infects people) - Affects only a certain population that live in Papua New Guinea. It is a neurological disorder that is caused by prions. Its symptoms are not being able to stand or walk without support that progresses to not being able to sit without support, uncontrollable bouts of laughter and eventually the person ends up wasting away and dying. Creutzfeldt-Jakob Disease (CJD) - Basically the human form of Mad Cow Disease; Neurological disease with symptoms of an altered behavior.

How do people acquire kuru?

Kuru is another human prion disease that is acquired through eating something that has the misfolded protein. It is restricted to a particular tribe living in Papua New Guinea which is off the northern coast of Australia. The symptoms of kuru are behavioral changes, inability to walk/sit until eventually the person ends up wasting away and dying. When the disease was first described, it was suspected very strongly that it's a purely genetic disease because it was restricted to one population of people. The majority of the people (75%) that got infected within that population were directly related to someone else that also have the disease. Mostly women and children were affected so maybe something on the X chromosome was responsible for spreading the disease. But actually, it was a particular custom and not genetics that was causing the spread of kuru. Whenever a relative passes away, the custom was that the women eats the relatives flesh and the children in the house would also get some of that food.

Name two examples of prion diseases in animals.

Mad Cow Disease (aka Bovine Spongiform Encephalopathy or BSE)- neurological disease with major symptoms for the cow such as an altered behavior and altered gait so it can't walk properly anymore. Scrapie (first prion disease that was ever described) - Sheep with an altered behavior that makes the animal scratch themselves against fence posts so sheep becomes inflicted and has bald spots

Prion disease can be transmitted from one animal to another (i.e. it's an infectious disease). What makes prion disease different from any other type of infectious disease?

Other infectious disease involve genetic components while prions do not, and are caused by just proteins that misfold in the brain

What is PrPC, and what does "PrPC" stand for?

PrPC is the normal form of PrP that is found in healthy brain cells. It stands for prion protein, cellular form.

Describe the difference in shape/appearance between PrPC and PrPRes.

PrPC: -Dominant 2° structure: more alpha helices (more curly) -Dominant 4° structure: monomer (found by themselves) -digested by proteinase-K? (enzyme categorized as protease which cleaves proteins): Yes PrPRes:-Dominant 2° structure: Beta sheets (flat broadsheets) -Dominant 4° structure: aggregate -digested by proteinase-K? (enzyme categorized as protease which cleaves proteins): No **If you unravel both amino acid sequences, they would be completely similar

PrPRes is also known as what?

PrPRes is also known as PrPSc, which stands for prion protein scrapie form. They are both interchangeable and refer to the misfolded version of PrP. It's named after this disease because it was the first animal prion disease ever described.

What is PrPRes, and what does "PrPRes" stand for?

PrPRes is the misfolded form of PrP. This is the diseased and infected version. PrPRes stands for prion protein resistant enzyme degradation. The enzymes that normally break down other proteins end up not breaking down the misfolded version of PrP so it's a lot more resistant to being broken down by certain enzymes and it's a lot more resistant to becoming denatured.

Describe what basically occurs during prion disease. Be sure to talk about PrPC and PrPRes in your description.

Prion disease occurs when PrPC is converted to PrPRes. The misfolding occurs in smaller discrete steps that form a molecule that looks different (which is still unknown) and forms another different looking molecule and that misfolds and forms another different looking molecule until eventually there's enough misfolding to produce PrPRes. It is thought that the PrPRes itself that doesn't actually cause the toxicity to the brain but probably one of the yet to be identified intermediates that's causing the neurological damage.

13) What tends to happen when PrPRes comes into contact with PrPC?

So if someone ate some meat with PrPRes in it, when you eat food, it gets digested in the stomach and the nutrients enter the blood by passing through the small intestine. The blood travels throughout the body including, the brain. There are very few things that can pass through the capillaries to enter the brain. The capillaries are very stringent on what kinds of molecules they allow through and they let glucose which feeds the brain cells. There is a blood-brain barrier that protects the brains from harmful molecules. Once the PrPRes gains access to the brain, they also have access to each individual brain cells. The PrPRes binds to PrPC and cause them to take on the misfolded shape. Some people seem to be more genetically predisposed to having the PrPC to become misfolded whenever they are in contact with PrPRes, like in kuru. • Contact with PrPRes aggregate causes PrPC to misfold • Some people/animals have versions of PrP that's more susceptible to misfolding

Describe three ways that a person/animal can become infected with prion disease

Spontaneous occurrence of misfolding of PrP: The person/animal doesn't have to do anything, their PrPC just spontaneously misfolds into PrPRes. Ex: sporadic forms of CJD and Gerstmann Straussler Scheinker Syndrome. Having version of PrP gene that encourages misfolding: There are slightly different alleles of PrP gene so depending on the allele/gene you inherit, you may/may not be more susceptible to having PrP protein misfold. Ex: fatal familial insomnia in people so the major symptom of FFI is the inability to sleep so that eventually ends up killing the person. Contact with PrPRes (most common): Having contact with the misfolded protein can cause someone or an animal to end up getting prion disease. Ex: mad cow disease (it used to be common practice that when a cow dies, you use that cow and grind it up to feed your other cows to save money on food and this includes the brain), variant CJD (acquired by eating/ingesting the misfolded protein), kuru (acquired by eating materials that have the prion protein PrPRes)

Describe an experiment/observation that backs up your answer to part a.

The elk with prion disease and the mice genetically engineered to express human PrPC causes a small amount of mice to have some of the elk protein spontaneously fold in a different way, which is similar to the mouse PrPC.

How do cows acquire mad cow disease (BSE)?

The epidemic is thought to have spread through the practice that if you have cows and one of them end up dying, you use that cow and feed it to the other cows to save money on food. It is a lot less common nowadays because it's been identified that it is how mad cow disease is spread

Describe the general appearance of a person or animal's brain that's infected with prion disease.

The general appearance of a brain that is infected with prion disease is that there are holes/blank areas/white spots that are actually accumulations of the protein that has become misfolded in the brain. Again, the misfolded proteins cause an altered neurological function. The brain looks like a sponge because of all the holes within the brain.

What type of molecule is PrP?

The specific protein that misfolds during prion disease is PrP. It is thought to play a role in signal transduction, which is whenever a cell receives a signal externally, and after receiving that signal, the cell does a lot of things and eventually cause the cell to respond to that signal. The misfolded PrP has a different shape so it no longer gets inserted into the membrane but instead is kind of clump together and form aggregates, which is shown as the big white holes in the general appearance of the brains.

All human prion diseases involve the same protein - PrP. Given that, explain how human prion diseases can vary from one another.

The white plaques formed in the brain have different patterns in different prion diseases (kuru, FFI, CJD, etc.)

How do people acquire fatal familial insomnia?

There are different alleles/genes that you can inherit and depending on which one you inherit, you may or may not be more susceptible to having your PrP protein misfold. People acquire FFI through a genetic predisposition.

How do people acquire variant Creutzfeldt-Jakob Disease (vCJD)?

This is acquired through eating contaminated materials. The vCJD is commonly thought to be acquired through eating foods like beef that have the mad cow protein in it.

What's another term used for "prion disease"?

Transmissible Spongiform Encephalopathies [TSE] (because the brains of people/animals that are infected with prion disease looks like a sponge). The "Spongiform Encephalopathies" mean that it is a disease that makes the brain look like a sponge while "Transmissible" means that it is a disease that can be transmitted between animals or between people. ex: Another term for Mad Cow Disease is Bovine Spongiform Encephalopathy or BSE

True or False. Suppose that you have a tube containing one million PrPC proteins, all taken from the same animal. Suppose also that all of these proteins misfold to produce one million PrPRes proteins. If you could take a close look at all the newly-created PrPRes proteins, it's possible that you'll find some of them that have a slightly different shape than the others

True

Where is PrP normally found?

Within the membrane of all normal, healthy brain cells

Is it possible for a prion-infected animal to transmit prion disease to an animal of a different species? Explain your answer.

Yes because there has been mice genetically engineered to express sheep PrPC. The transmission between species is difficult but not impossible. Only 2 of the 29 mice developed detectable levels of PrPRes in the brain. The type that people are concerned with are cows and people. So animal with mad cow disease was fused with mice genetically engineered to express human PrPC and resulted in 1 out of 4 mice developed detectable levels of PrPRes in the brain. Infecting PrP must be similar to host PrP for misfolding to occur. If PrP from different animal does cause disease, it becomes progressively easier to pass on with continued passage within same species.

Describe two characteristics that are common to all prion diseases.

involve neurodegeneration (major symptoms in all prion diseases are altered behavior and altered motor function) AND are caused by proteins that misfold in the brain (causative agent of prion doesn't have genetic components)