A key discovery about how prions - mysterious morsels 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, according to the two Florida State University scientists who led the study, are 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 findings, says Donald Caspar, a structural biologist based in FSU's Institute of Molecular Biophysics, imply that the accepted theory that DNA is the basis of all heredity, including the transmission of deadly diseases, might have to be revisted.
The two scientists Chih-Yen 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 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 hypothesised 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 therefore 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 fibre-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 fibres are the primary causes of infections, not the result of them.
Full findings are described in the 18 March issue of the journal Nature.