Kuru prion questions

[RedAlert]

I am doing research on the Kuru disease now, which I learn is caused by a prion, and infectious protein.

 

Now what I'd like to know is that what exactly does the prion do that causes the different brain problems? One thing I read on Wikipedia under the Prion article is that the PrP^Sc protein which is somewhat similar to the HuPrP^Sc (kuru prion protein) contains a lot more of a amino acid structure called "beta sheet". This beta sheet causes amyloid aggregation.

 

Now what exactly is amyloid aggregation? The article for amyloids in Wikipedia didn't tell me much apart from the fact that it's plays a role in certain brain diseases, and that it's thin, fibrous and made up of proteins. That's how I understood the first sentence (which is really the important sentence). Would I be correct?

 

So the HuPrP^Sc protein forms these long fibrils because of these beta sheets, and that causes many problems in the brain. I understood this bit from this site: http://www.ibridgenetwork.org/technology.asp?sID=01E525E2E6BC4B6EA4F69D25DBE7AF5F&page=1361. This is the paragraph that is important:

 

"Conformational diseases," share a common etiology whereby proteins fold irregularly to produce structural flaws. These flaws result in the proteins unnaturally aggregating and thereafter precipitating as fibrils from their solvents. Such solvents include blood, urine, water, lymph, cerebrospinal fluid, and other physiological fluids. Diseases such as sickle cell anemia, amyloid light chain disease, senile systemic amyloidosis, Alzheimer's, and prion encephalopathies including kuru and "mad cow" disease or BSE, are the result of protein conformation anomalies.

 

So why are these fibrils dangerous? What problems do they cause? I can't seem to find that information on Google, because it's buried under loads of scientific jargon that complicates it a lot, and leads to me to research a lot of other different things. I tried doing spending quite a bit of time on it (some 4-5 hours) but I didn't come up with anything worthwhile on the issue. I did a search on Wikipedia (thank god for wikipedia) and got that the fibrils cause problems in blood vessels, which can increase the risk of hemorrhagic stroke. But is Alzheimer's even a prion disease? Would the same thing occur in Kuru? I have not read of any hemorrhagic strokes under the symptoms for Kuru. So how would these prions affect a person's brain exactly in Kuru? What do they do to the nerve cells?

 

I'd really appreciate help in this matter from someone who is well versed in the subject.

[scicop]

I am doing research on the Kuru disease now' date=' which I learn is caused by a prion, and infectious protein.

 

Now what I'd like to know is that what exactly does the prion do that causes the different brain problems? One thing I read on Wikipedia under the Prion article is that the PrP^Sc protein which is somewhat similar to the HuPrP^Sc (kuru prion protein) contains a lot more of a amino acid structure called "beta sheet". This beta sheet causes amyloid aggregation.

 

Now what exactly is amyloid aggregation? The article for amyloids in Wikipedia didn't tell me much apart from the fact that it's plays a role in certain brain diseases, and that it's thin, fibrous and made up of proteins. That's how I understood the first sentence (which is really the important sentence). Would I be correct?

 

So the HuPrP^Sc protein forms these long fibrils because of these beta sheets, and that causes many problems in the brain. I understood this bit from this site: http://www.ibridgenetwork.org/technology.asp?sID=01E525E2E6BC4B6EA4F69D25DBE7AF5F&page=1361. This is the paragraph that is important:

 

[i']"Conformational diseases," share a common etiology whereby proteins fold irregularly to produce structural flaws. These flaws result in the proteins unnaturally aggregating and thereafter precipitating as fibrils from their solvents. Such solvents include blood, urine, water, lymph, cerebrospinal fluid, and other physiological fluids. Diseases such as sickle cell anemia, amyloid light chain disease, senile systemic amyloidosis, Alzheimer's, and prion encephalopathies including kuru and "mad cow" disease or BSE, are the result of protein conformation anomalies. [/i]

 

So why are these fibrils dangerous? What problems do they cause? I can't seem to find that information on Google, because it's buried under loads of scientific jargon that complicates it a lot, and leads to me to research a lot of other different things. I tried doing spending quite a bit of time on it (some 4-5 hours) but I didn't come up with anything worthwhile on the issue. I did a search on Wikipedia (thank god for wikipedia) and got that the fibrils cause problems in blood vessels, which can increase the risk of hemorrhagic stroke. But is Alzheimer's even a prion disease? Would the same thing occur in Kuru? I have not read of any hemorrhagic strokes under the symptoms for Kuru. So how would these prions affect a person's brain exactly in Kuru? What do they do to the nerve cells?

 

I'd really appreciate help in this matter from someone who is well versed in the subject.

 

 

Ok, Prion Disease and Alzheimers are two different puppies, however, they share in common the notion that at some point in protein synthesis/degredation there is a failure of the cell to clear misfolded proteins which can accumulate in the cell and cause cytotoxicity.

 

About Alzheimers, there are two proteins that are linked to the accumlation of proteins inside the cell. One is Tau. The other is Beta-amyloid.

To keep it simple, in Alzheimers two things occur:

 

1. there is an uncontrolled hyper-phosphorylation of Tau (a microtubule associated protein) that accumulates and precipitates inside the cell. The mechanism for the onset of such hyperphosphorylation is still being explored but see work by Eckard Mandelkow, PhD, and Ken Kosik, MD. Such precipitation is toxic. The precipitated hyper-phosphorylated tau is known as neurofibullary tangles or just tangles, if you're in the field.

 

2. Beta-amyloid. Beta-amyloid is a cell surface molecule of unknown function. It is proteolytically processed post-transcriptionally by a number of proteases called "secretases", the they are known as alpha, beta, gamma, ..and i think there is a sigma now. Presenillins have also been shown to be involved. One of the secretase proteases, the gamma-secretase, has been linked to the improper cleaving of Beta-amyloid. When this occurs, it has been suggested that abnormal cleaving of Beta-amyloids causes it to become insoluable, and thus it precipitates both inside and outside the cell. This, causes the build up of "amyloid" plaques (so in the field plaques referes to amyloid build up). The toxicity behind amyloid build up has been linked to the formation of reactive oxygen species that occure as a result of such build up. Furthermore, there is question as to whether soluble forms of improperly cleaved Beta amyloids are toxic as well (see work by Rudy Tanzi, PhD). Pharmacotherapies based on secreatase inhibition are in the pipeline of some pharmas.

 

These plagues and tangles are visible under regular light microscopy. As a result of they cytotoxicity, they create "holes" in the brain..this is why certain areas of the brain of an Alzheimers patient can look like swiss cheese.

 

So the take home message is that there is an accumlation of protein (although the initiating factors are still being dissected) that is cytotoxic to the surrounding cells, thus causeing demensia. Scientist have identified cells that produce acetylcholine are most affected by plague and tangles, and acetylcholine replacement is the mainstay anti-dementia therapy for Alzheimers Disease patients, note it is not curative.

 

Prions, like Alzheimers, accumulate inside the cell (presumably through self replication and high jacking of the cells protein syntheis machinary). There is an inability of the cell (through its degredation pathways) to clear the protein build up. Thus the accumulation of the proteins become cytotoxic (which can involve to promotion of reactive oxygen species buildup, which can really damage the cell..i.e. lipidperoxidation, dna damage, etc). I don't need to mention this ..but see work by Stanly Prussner, nobel prize laureate for identifying and promoting the theory of prions.

 

I've tried keeping it pretty simple but if you have more questions ask. Look up those names I gave you in pub-med..those are some of the big names in Alzheimers research!!!

 

Also check out http://www.aging-institute.org.....a colleague of mine runs that institute (the executive director) and he's got some great info on the site.