Milk, Prions and Evolution

ResearchBlogging.orgPrion protein (PrP) is the focus of some neurodegenerative diseases. It is believed that misfolded prion protein (PrPsc, or “scrapie”) is the infectious agent responsible for bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jacob disease (CJD), among others. PrPsc propagates by conversion of normal (healthy) prion protein (PrPc).

Several questions arise in the research community. Two of them are: a) can prions be transmitted from domestic animals into humans, and b) how the prion protein propagates inside a healthy subject. Food safety is a major concern. Milk and their derivatives are a subject of study, because of their wide consumption in most countries. A study [1] from Didier and coworkers shows that the normal prion protein is detected in mammary gland and milk fractions of cow, goat and sheep. PrPc protein is detected in all milk fractions (skimmed milk, acid whey, cream) in goat and sheep. Although the authors failed to detect PrPc in bovine milk, they refer to other study that successful detected the protein in bovine milk using a different approach. Some conclusions of this study are that analytical methods to detect the prion protein should be improved (hopefully, at an industrial scale), to avoid the variability between studies, specially considering the high levels of prion protein detected in cream fractions and the widespread use of cream in cooking.

Scrapie in milk?

Another conclusion is that the prion protein exist at low levels in mammary gland and milk. Even detecting PrPc in milk requires hard work (enrichment of protein concentration, for example). But someone expect that PrPsc should exist at even lower levels, specially in asymptomatic animals. Then, PrPsc can be undetected in an industrial quality control. What happens if the common assumption that infectious prion protein is not present in milk is wrong? There is evidence of infectious prion transmission via milk; Timm Konold and colleagues published evidence in lambs fed with infected and healthy milk, but using lambs from a genotype with high susceptibility to scrapie [2], observing high levels of infection. Thinking in human population, if  populations with genetic susceptibility to scrapie are identified, then health measures should be implemented in those populations to avoid the exposure to potentially contaminated milk and cream.

Once inside the cell, then what?

A few days ago, a comment in Science raised the question  “What makes a prion infectious?” [3]. The article referred to two papers published recently. One of them raises interesting questions regarding the possibility of disease development after drinking contaminated milk, for example. A research team from the Department of Infectology in the Scripps Institute, showed that prions in cell culture are able to “evolve” [4]. Prions, viewed as infectious agents, exists as strains, which are a specific conformer of the protein, and they are able to multimerize forming seeds. One hypothesis, called “protein-only”, assumes that each strain is associated with a different conformer of PrPsc, and the infectious agent is composed of a misfolded conformer exclusively (without cofactors). Many strains can exist, since many conformers are able to arise from PrPc misfolding. Experiments from the work of Li and colleagues shows that, indeed, these strains exist, and they were able to identify prions strains sensitive to swainsonine (inhibitor of the formation of N-linked glycans). In a series of experiments they showed that the strains identified in a time-lapse isolated from a cell line infected with a brain homogenate changed over time: in the first days, they identified swa-resistant strains (and competent for R33, a neuroblastoma-derived cell line), but then they identified swa-insensitive and R33-incompetent, after they transferring to PK1 cells. These and remaining experiments suggests that the prion population changed over time, and there are different strains that can “compete” if the growth conditions are advantageous to a specific strain.The authors, based in their results, conclude that prions show the hallmarks of Darwinian evolution: they are subject to mutation and to selective amplification. Obviously, these findings are relevant to Medicine, since drug discovery should consider the fact that, in disease conditions, the raise of a infectious prion can lead to mutation (more likely by binding of a prion to some cellular cofactor leading to a small variations in the misfolded structure) of some monomers, causing strain evolution, some of which can growth in the presence of some drug, replace the remaining strains and lead to resistance.

It is evident that we are far from understand the biochemical and molecular foundations of scrapie disease and mechanism, and the new evidence suggest a complex scenario, specially regarding to the deveolpment of new drugs to fight the clinical symptoms and the CJD and BSE diseases.

References

[1] Didier A, Gebert R, Dietrich R, Schweiger M, Gareis M, Märtlbauer E, & Amselgruber WM (2008). Cellular prion protein in mammary gland and milk fractions of domestic ruminants. Biochemical and biophysical research communications, 369 (3), 841-4 PMID: 18325321

[2] Konold T, Moore SJ, Bellworthy SJ, & Simmons HA (2008). Evidence of scrapie transmission via milk. BMC veterinary research, 4 PMID: 18397513

[3] Supattapone S (2010). Biochemistry. What makes a prion infectious? Science (New York, N.Y.), 327 (5969), 1091-2 PMID: 20185716

[4] Li J, Browning S, Mahal SP, Oelschlegel AM, & Weissmann C (2010). Darwinian evolution of prions in cell culture. Science (New York, N.Y.), 327 (5967), 869-72 PMID: 20044542

Advertisements

0 Responses to “Milk, Prions and Evolution”



  1. Leave a Comment

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




Featured Posts




astuscience’s Twitter

Error: Twitter did not respond. Please wait a few minutes and refresh this page.

Archives

Listed on

Subscribe

Add to Technorati Favorites
Pablo Andrés Astudillo on Labmeeting

RSS Peer Review on Science Blogs

  • An error has occurred; the feed is probably down. Try again later.

RSS Science News

  • An error has occurred; the feed is probably down. Try again later.

RSS Cell

  • An error has occurred; the feed is probably down. Try again later.

RSS PLOS Biology

  • An error has occurred; the feed is probably down. Try again later.

RSS Nature News

  • An error has occurred; the feed is probably down. Try again later.
Life Science Blogs - BlogCatalog Blog Directory

Calendar

March 2010
M T W T F S S
« Jan   May »
1234567
891011121314
15161718192021
22232425262728
293031  

RSS PHD Comics

  • An error has occurred; the feed is probably down. Try again later.