jump to navigation

How do prions work? November 21, 2006

Posted by Hegemony in Health, Science.
trackback

Prion diseases operate differently than any other class of disease we are currently aware of. It is reliant on mutated forms of a common mammalian protein known as prion protein (PrPc). PrPc is highly homologous among mammals. In humans this protein is expressed in the central nervous system as well as in leukocytes and the gut. Common diseases known to be prion in nature include kuru, scrapie, Creutzfeldt–Jacob disease (CJD), Bovine Spongiform Encephalopathy (BSE/”mad cow”), and Gerstmann Straussler Scheinker (GSS) disease. Prion diseases are unique also in that there are three known ways for one to contract them: infectious, inherited, and sporadic.

A modified prion protein (PrPsc) has properties very different from those of the unmodified PrPc. PrPsc is highly resistant to the enzymatic degradation of the ubiquitin-proteasome system causing them to build up. This is a result of the changes in the secondary structure of PrPc, that is PrPsc has many areas of alpha helixes converted to beta sheets. These proteins build up in the brain causing cell death.

When a PrPsc molecule in introduced into a healthy animal it causes conformational changes in the healthy PrPc forms of the protein. This process is known as “Pruisner’s Theory”. This theory is evidenced by the tendency of aggregates to resemble the primary structure of the PrPc of a particular organism.

Recent studies have hinted that PrPsc aggregates are not necessary for prion-related neurotoxicity. If proteins are non-functional they are tagged by ubiquitin and degraded in a proteasome. This goes for PrPc as well. It has been discovered that if the ubiquitin-proteasome is inhibited, misfolded PrPc will build up in the cytosol and cause classic prion-related neurotoxicity. These PrPc proteins will aggregate in the cytosol and cannot be cleared by reinitializing the ubiquitin-proteasome system.

There are several findings in mouse studies that must be taken into consideration when thinking about the role of PrPsc in disease. It cannot cause disease when no PrPc is present. In a study mice with out the PrP gene (prpn) the PrPsc was unable to cause disease. Mice with truncated prpn producing non-functional PrP have high levels of cytosolic PrP and have massive neuronal loss. Older mice can spontaneously develop these symptoms, presumably sporadically. If PrPc production is inhibited in early PrPsc infection symptoms will not develop. The concentration of PrPsc does not seem to have an effect on the severity of the disease.

The new research raises many questions about the role of PrPc in relation to PrPsc exposure. It seems clear that PrPsc converts PrPc to the highly toxic form. However, it also seems clear that PrP itself can contribute to disease if the ubiquitin-proteasome system is not working properly.

It is put forth by researchers that the introduction of PrPsc may not be the determining factor in the development of neurodegenerative symptoms. This could be caused by a defect in the processing or metabolism of PrPc, or in the prpn gene itself. They state that an exogeneous form of PrPsc may initiate the events leading to the build up of PrPc in the cytosol and that this PrPc may fuel the further accumulation of PrPsc aggregates. This process may actually explain infectious, inherited, and sporadic prion disorders.

 

About these ads

Comments»

1. SS - April 10, 2008

do prions have any contribution in the amyloidosis disease?

2. Saima Asad - May 18, 2009

Do prions move? Do they acquire nutrients and how? How do they reproduce?

3. Ryan - May 27, 2009

Prions are nonliving proteins so they do not need nutrients or reproduce. they would simply be replicated with the rest of the genome.

Hegemony - May 27, 2009

As I said above, the indications are that malformed PrP actually cause healthy PrP to undergo conformational changes. Prions are “replicated” from the supply of normal PrP. This is, of course, still theoretical.

4. Andi - August 30, 2009

How could the immune system be stimulated to recognise the prions as damaging and attack them? have heard that they are running clinical trials in Italy using Doxycycline which is a teracycline drug to slow the progression of the illness. How is this possible given the theorized behaviour of the prion?

Hegemony - August 30, 2009

The problem is that these are the body’s own proteins. Malformed, but still “self”. The main conformational difference is that the prions have beta sheets where they shouldn’t. Trying to train the immune system to recognize these malformed proteins would have a serious risk of causing autoimmune disorder.

Even if a proper immune response could be produced, there’s little the immune system could do to clear prions. They resist degradation and could just convert more PrP in macrophages if phagocytosed. I suppose the best you could hope for is inactivation via antibody binding.

I have not heard of that research. I’m not sure how an antibiotic could have any effect on prions. If you have a Journal article to cite, I’d have a look.

5. Sinead - December 10, 2010

Hello, I am writing a dissertation on prions and would really appreciate the references you have used in writing this article; especially those relating to the theory PrPsc may not be the determining factor in TSEs and the study with the mice.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Follow

Get every new post delivered to your Inbox.

%d bloggers like this: