Prions are fascinating proteins – though their composition doesn’t change, they can adopt two shapes. One shape is innocuous; the other shape causes disease, such as scrapie in sheep, bovine spongiform encephalopathy in cattle (mad cow disease) and Creutzfeldt–Jakob disease in humans. These are incurable conditions where cells in the brain die, causing progressive dementia and death; upon examination, the brain is full of holes, like a sponge (hence the term ‘spongiform’).

In 1997 Stanley Prusiner won a Nobel Prize for discovering the prion protein and how its abnormal shape causes disease. However, we still don’t understand the function of the normally shaped prion protein, which is found throughout nature, in mammals, fish, yeast and fungi.

A new study using the zebrafish, a freshwater fish commonly used in developmental biology research, suggests that the normally shaped prion protein plays a crucial role in controlling how cells touch each other and communicate.

Edward Málaga-Trillo, Gonzalo P. Solis and colleagues from the University of Konstanz in Germany injected modified DNA into zebrafish embryos to reduce production of the two zebrafish prion proteins. When researchers reduced levels of prion protein 1, the embryos stopped growing during the gastrulation stage, when precursors to tissues and organs are formed. When researchers reduced levels of prion protein 2, the embryos developed beyond gastrulation and survived for several days, but had malformed brains and eyes. Producing more prion proteins than normal caused similar anatomical problems.

These defects could be rescued by injecting the modified DNA together with DNA that instructs cells to produce normal copies of prion proteins (with normal shapes). Even prion protein from mice could rescue development in zebrafish, suggesting that prion proteins from different animals have similar functions.

Further experiments showed that low levels of prion protein 1 cause cells in the embryo to lose their polygonal shape, become round, and detach from normally adherent cells. This abnormal cell shape and behavior likely caused the embryo to stop growing.

These results suggest that in zebrafish, prion proteins are required for normal development. Since zebrafish development is similar to mammalian development, it is likely that prions play a crucial role in the development of human embryos as well.

That’s the conventional ending, but this story has a twist. In 1992, scientists used genetic tricks to develop mice that were missing the prion protein. These mice “develop and behave normally.”

If zebrafish and mice are so similar, how do we explain this discrepancy?

It’s possible that when it comes to prions, zebrafish and mice are different. One argument is that prions are not essential for mouse development. This is the opinion of the committee that awards the Nobel Prize, which wrote “strangely enough, mice lacking the prion gene are apparently healthy, suggesting that the normal prion protein is not an essential protein in mice, its role in the nervous system remains a mystery.” However, this would not explain why prions from zebrafish and mice are similar, or why adding mouse prion can rescue zebrafish embryos deficient in zebrafish prions.

The other argument is that prions are so important for normal development that mice evolved redundancies, other proteins, not prions, that perform similar functions as prions. Málaga-Trillo and colleagues favor this idea, though it’s not clear why zebrafish lack an analogous backup system.

As with all good results, more research is required.

Source: “Regulation of Embryonic Cell Adhesion by the Prion Protein” by Edward Málaga-Trillo, Gonzalo P. Solis, Yvonne Schrock, Corinna Geiss, Lydia Luncz, Venus Thomanetz and Claudia A. O. Stuermer, published March 10 in PLoS Biology (doi:10.1371/journal.pbio.1000055).