Proteins Alone Can Spread Infections; Implications

Released: Mon 15-Mar-2004, 15:50 ET
Embargo expired: Wed 17-Mar-2004, 13:00 ET

Newswise — A key discovery about how prions - mysterious bits of protein thought to be the cause of mad cow disease and
similar brain disorders - infect healthy cells is being hailed by scientists as a breakthrough in the quest to
understand the role of these proteins in neurological diseases.

The findings by two Florida State University scientists are described in the March 18 issue of the journal Nature.

What they found, according to co-discoverer Chih-Yen King, is the "first definitive proof" that prions can transfer
heritable traits from one living system to another without the help of gene-carrying DNA or its cousin RNA, compounds
called nucleic acids.

The finding means that what school kids have been taught for decades - that DNA is the basis of all heredity, including
the transmission of deadly diseases - now must be revisited, says Donald Caspar, a structural biologist based in FSU's
Institute of Molecular Biophysics. King and his co-discoverer, Ruben Diaz-Avalos, are post-doctoral scientists in
Caspar's lab.

King and Diaz-Avalos, working with yeast cultures, isolated and identified three different strains of yeast prions,
each of which were found to originate from the same protein molecule that, for reasons yet unknown, turned into
infectious prions. The team found that these all-protein particles act like genes in transferring life-changing
information in yeast cells without relying on DNA or RNA as the information carriers.

Work by Jonathan Weissman at the University of California, San Francisco, whose research also appears in Nature,
reached the same conclusions as the FSU scientists, albeit from a different angle. Also using yeast cultures as a
model, Weissman's group isolated and identified two distinct yeast prion strains caused by "protein-only" prions.

Collectively, the research helps resolve the most puzzling question in prion research, King said. Since prions were
first hypothesized in 1982 by Stanley Prusiner, a professor at UCSF, the curious particles have been implicated in a
variety of degenerative neurological diseases, ranging from scrapie in sheep to the now well known bovine spongiform
encephalopathy, or mad cow disease, that can be passed on to humans with lethal consequences.

Scientists thus reasoned that prions came in multiple strains, just like viruses, capable of producing different
symptoms in host animals. But unlike viruses, which essentially are tightly coiled packages of DNA or RNA, exhaustive
analysis never found even the slightest trace of nucleic acids in prions. Many scientists could not imagine any way for
an infectious agent to affect host animals in different ways without using DNA to pass along different sets of
instructions to living cells.

Even after Prusiner won a Nobel Prize for Medicine for his ground-breaking prion work in 1997, many scientists were
still skeptical that his "protein-only" theory - that prions could act as agents of heredity all on their own without
the benefit of DNA - would hold up.

"Prusiner had a lot of very strong circumstantial evidence, but no rigorous proof," said King. "People speculated that
the nucleic acid was there, you just couldn't find it. Our research shows, convincingly, unambiguously, that you have
strains that (consist of only) one protein, just folded differently."

Using yeast as a model because of its reproductive speed and its safety (yeast prions are harmless), King and Diaz-
Avalos demonstrated that prions act much the same way in yeast as they apparently do in mammals.

When introduced into healthy cells, so-called "misfolded proteins" (or prions) seek out and find certain proteins that
are identical to the proteins from which they were originally made. Contact with the invading prions causes healthy
protein molecules to warp into the same "misfolded" pattern as their attackers, thereby becoming prions themselves.
Invariably, this leads to the disruption or alteration of normal cell function, King said.

Another key find in the FSU study is that prions formed in host cells are amyloids, a family of fiber-forming proteins
that often are associated with neurological disorders in humans. Amyloid plaques in human brain tissue, for example,
are a well-known component of Alzheimer's and Parkinson's diseases. Scientists have long debated whether such plaques
are merely a symptom of such diseases or a cause.

King says his work proves that, at least in yeast cultures, amyloid fibers are the primary causes of infections, not
the result of them.

"Amyloids (in yeast) we now know are not the end-product of the infection - they're the cause," he said.

Source: Florida State University
For more stories about research at FSU, visit our news site at http://www.fsu.com

SOURCE: Newswise (press release)
http://www.newswise.com/p/articles/view/503734/

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