All previously known pathogens, such as bacteria and viruses, contain nucleic acids, which enable them to reproduce. The prion hypothesis explained why the mysterious infectious agent is resistant to ultraviolet radiation, which breaks down nucleic acids, but is susceptible to substances that disrupt proteins.
Some scientists hypothesized that the distorted protein could bind to other proteins of the same type and induce them to change their conformation as well, producing a chain reaction that propagates the disease and generates new infectious material. Since then, the gene for this protein has been successfully cloned, and studies using transgenic mice have bolstered the prion hypothesis.
The evidence in support of the hypothesis is now very strong, though not incontrovertible. First, the mounting experimental evidence has generated great interest in what appears to be a totally new kind of mechanism of disease. Second, the demonstration that prions are responsible for 'mad cow' disease bovine spongiform encephalopathy , which has infected large numbers of cattle in Great Britain and panicked the public, has lent new urgency to the quest for a cure--especially since the discovery that infected cows might be responsible for several new cases of CJD in humans.
Finally, I and my colleagues have recently determined that a phenomenon much like prion infection exists in yeast. These genetic traits had been known for many years, but their baffling patterns of inheritance for example, they can be passed along through a cell's cytoplasm, rather than the nucleus where the DNA resides had eluded explanation. We now know that the genetic trait is transmitted by proteins that are encoded in the nucleus but that can change their conformation in the cytoplasm.
Once this change has occurred, the reconfigured proteins induce other newly made proteins of the same type to change their conformation, too. Molecular genetic research on yeast should speed up the resolution of fundamental questions about the workings of protein-folding chain reactions.
And more important, it suggests that the prion mechanism is ubiquitous among living things and may be responsible for many phenomena other than neurodegenerative diseases like CJD. Mark Rogers in the department of zoology and the Biotechnology Centre at University College, Dublin, adds some further information:.
Prusiner of the University of California School of Medicine at San Francisco in to distinguish the infectious agent that causes scrapie in sheep, Creutzfeldt-Jakob disease CJD in humans and bovine spongiform encephalopathy BSE in cattle from other, more typical infectious agents.
The prion hypothesis postulates that these diseases are caused not by a conventional virus or bacterium but by a protein that has adopted an abnormal form.
Recently scientists have developed a molecular model of both variants and have published papers describing the structure of prion proteins as manufactured by E. Further work using magnetic resonance imaging and x-ray crystallography should help us understand the key structural elements that allow the prion to co-opt the normal cellular form into the disease-producing variant.
However, due to the long incubation period of Kuru, there continued to be cases among the elderly into the s probably because they contracted the disease much earlier in life. For his discoveries, Gajdusek was awarded the Nobel Prize in Medicine in Working at the University of California at San Francisco, Prusiner voraciously pursued the available literature on CJD and its related illnesses and collaborated with other scientists to try to purify the agent responsible for these peculiar diseases Their efforts met with failure, and Prusiner lost his experimental funding from the Howard Hughes Medical Institute due to the seeming hopelessness of his work However, after finding support from other sources and continuing his research, it occurred to Prusiner that his inability to purify a virus responsible for scrapie might be because there was no virus to be found Perhaps he had uncovered an entirely new form of infection!
For his contributions to the field, Pruisner was awarded the Nobel prize in Medicine and Physiology in In response to this discovery, UK officials placed regulations on feed content. However, it appeared the regulations had been applied to laxly, and in , inadequate precautions in British slaughterhouses were linked to a variant of CJD that had appeared in patients much younger than was typical for the disease Later, epidemiological studies suggested that the disease had originated from an antelope imported from South Africa to a British safari park in the s Scientists believe that the infected antelope was ground into cattle feed, transmitting the prions responsible for vCJD to herds of cows and ultimately to humans.
The disease led to a ban by the European Union EU of beef import from Britain that lasted for 10 years. During the s, no significant advances regarding the nature of the agent were made, that is, not until Stanley Prusiner took on the problem.
Prusiner set out to purify the infectious agent, and after 10 years of hard work he obtained a pure preparation. To his great surprise, he found that the agent consisted only of a protein, which he named prion, a term derived from proteinaceous infections particle.
Strangely enough, he found that the protein was present in equal amounts in the brains of both diseased and healthy individuals.
This discovery was confusing and it was generally concluded that Prusiner must have arrived at the wrong conclusion. How could a protein cause disease if it was present both in diseased and healthy brains? The answer to this question came when Prusiner showed that the prion protein from diseased brains had a completely different three-dimensional conformation. This led Prusiner to propose a hypothesis for how a normal protein could become a disease-causing agent by changing its conformation.
The process he proposed may be compared to the transformation of Dr Jekyll to Mr Hyde — the same entity, but in two manifestations, a kind innocuous one, and a vicious lethal one. But how can a protein replicate without a genome? Stanley Prusiner suggested that the harmful prion protein could replicate by forcing the normal protein to adopt the shape of the harmful protein in a chain reaction-like process.
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