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Guardians gone astray –

A marriage of opposites lets neurons die

Munich, 07/02/2008

The folding of cellular prion protein (PrPC) into a pathological – i.e. disease-causing – conformation (PrPSc) is the characteristic feature of various neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, BSE in cows or scrapie in sheep. In these cases, PrPSc – with its wrong three-dimensional structure – accumulates and destroys nerve tissue. In its normal structure, however, PrPC protects cells against stress, and could also have other functions as yet unknown. An international team of researchers under the direction of Professor Jörg Tatzelt of Ludwig-Maximilians-Universität (LMU) München has now revealed online in “EMBO Journal” that the toxic effect of the misfolded prion protein only occurs in cells that also contain the normal prion protein. It could just be that the two proteins are forming a bond, and then causing cell death as a complex. “In order to be able to protect cells against stress, however, two normal prion proteins also have to form a bond, thus forming what is known as a dimer,” reports Tatzelt. “We have been able to identify which protein domains are required for dimerization and stress-protective activity. On the whole, our results could provide the starting point for therapies against prion disease.”

The two-faced Roman god Janus is nowadays the icon for ambivalence, and thus also for people who bear apparently incongruous characteristics. And yet it is in the world of molecules that Janus has found his perfect equivalent: the prion protein. This molecule comes in two different forms, depending on the three-dimensional structure it is folded into. Proteins are the most important functional elements in the cell. Newly synthesized, they consist of one or more long chains of amino acids, the building blocks of proteins. But they can only fulfil their duty once these chains have been folded into a very specific structure. In its correct form, the prion protein fulfils several important functions in the cell, one of these being to protect it against stress.

In a misfolded form, however, the prion protein can lead to deadly, so far untreatable neurodegenerative disease, such as Creutzfeldt-Jakob disease in humans, “mad cow” disease BSE or scrapie in sheep. The cause of these diseases went unknown for a very long time. It was only at the beginning of the 1980s that US researcher Stanley Prusiner offered the hypothesis that misfolded prion proteins could ‘force’ their correctly formed counterparts also into a wrong three-dimensional structure. This supposition contradicted a central dogma of biology, namely that only pathogens with a nucleic acid such as the genetic molecule DNA could spread infections. And yet, the number of clues largely corroborating Prusiner’s hypothesis of infectious proteins increased – and ultimately won him the Nobel Prize for medicine.

In their investigations, the researchers working with Tatzelt were able to confirm that the production of normal prion proteins could protect the studied neurons against stress. They were also able to demonstrate that the toxic effect of misfolded prion proteins is dependent on the normally folded, stress-protecting PrPC in the cell: in neurons lacking PrPC, the misfolded prion proteins cannot cause any damage. Presumably, the stress-protective activity of the normal prion protein depends on two such molecules forming a bond, or dimer in other words. The research team was also able to decipher which sections in the proteins are essential for this function. This included two hitherto unknown protein domains.

“We can now speculate that the misfolded prion proteins can only express their toxic effect if they form a bond with PrPC, to form a complex of one normal and one misfolded prion protein,” states Tatzelt. “But we still don’t know how such a complex of two mismatched partners can trigger cell death. We are now going to do further tests to investigate the signal chain. Our results, however, have already given us some important insights into the mechanism of the protective function of normal prion proteins, as well as into the pathological effect of their misfolded counterparts. Perhaps in future these insights will also be able to be applied as therapies against prion diseases.”


“Stress-protective signalling of prion protein is corrupted by scrapie prions”,
Angelika S. Rambold, Veronika Müller, Uri Ron, Nir Ben-Tal, Konstanze F. Winklhofer and Jörg Tatzelt,
EMBO J. 2008 Jun 19. [Epub ahead of print]


Prof.  Dr. Jörg Tatzelt
Adolf Butendandt Institute at LMU Munich
Tel.: ++49 (0) 89 / 2180 – 75 – 442 / – 458
Fax: ++49 (0) 89 / 2180 – 75 – 415


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