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【medical-news】神经退行性病变的元凶：感染性蛋
http://www.sciencemag.org/cgi/content/full/326/5958/1337
Neurodegeneration: Could They All Be Prion Diseases?
Greg Miller
Recent studies have renewed interest in the idea that many neurodegenerative diseases may involve prionlike mechanisms.
The idea that proteins can be agents of disease was once heretical, but two Nobel Prizes later all but the most die-hard skeptics have been convinced that misfolded proteins called prions are the cause of several neurodegenerative disorders in humans and other animals. In disorders such as scrapie, mad cow disease, and Creutzfeldt-Jakob disease, misfolded molecules of a naturally occurring protein act like bad role models, encouraging normally folded proteins to misfold and clump together. As aggregates of misfolded proteins spread through the brain, nerve cells stop working properly and eventually die.
A recent flurry of papers has revived interest in the idea that such mechanisms may play a role in an even wider range of neurodegenerative disorders, including two of the most dreaded scourges of old age: Alzheimer's and Parkinson's diseases. Such diseases almost certainly aren't contagious like true prion diseases are, at least in ordinary circumstances, but they may propagate through the nervous system in much the same way. The idea is actually decades old and seems to have originated with Daniel Carleton Gajdusek, who won a share of the 1976 Nobel Prize in physiology or medicine for his work on kuru, a prion disease he claimed was transmitted by ritualistic cannibalism among the Fore people of New Guinea. But until very recently, there was little experimental evidence for prionlike mechanisms in other neurodegenerative disorders, says Lary Walker, a neuroscientist at Emory University in Atlanta. "It's an old idea with new legs," Walker said in his introduction to a recent online seminar on this topic hosted by the Alzheimer Research Forum (Alzforum).
Evidence from recent animal studies suggests that many of the misfolded proteins thought to play a central role in a wide range of neurodegenerative disorders can, like prions, "seed" the misfolding and aggregation of their normally folded kin. In some cases, these pathological protein clusters appear to propagate from cell to cell. Such a mechanism could help explain several puzzles—such as why some neurodegenerative disorders tend to spread from one part of the nervous system to another in a characteristic pattern, and why some researchers have found pathological protein deposits in fetal stem cells transplanted into the brains of Parkinson's patients (Science, 11 April 2008, p. 167).
"Twenty, 30 years ago, when people were proposing these links, we didn't know that networks degenerate [in characteristic patterns], and we didn't have fetal transplants," says Marc Diamond, a neurologist at Washington University School of Medicine in St. Louis, Missouri. The prion concept helps integrate much of what's known about neurodegenerative diseases, Diamond says. "The reason it's catching on is that it makes a lot of sense." Like a growing number of researchers, Diamond thinks the prion concept may not only help researchers gain a better understanding of neurodegenerative diseases but also point to treatment strategies they might not have considered otherwise.
Killer proteins
The high prevalence of kuru in the Fore people is one of the great medical mystery stories of all time. The disease spread in a manner that suggested infection, yet it caused no fever or other inflammatory response. Gajdusek won the Nobel for his work suggesting that kuru was transmitted by cannibalism practiced as part of funeral rites among the Fore. But the infectious agent remained a puzzle. In laboratory experiments with infected brain tissue, the infectious agent survived heat, chemicals, and ultraviolet light that destroy the infectivity of viruses and bacteria.
In the early 1980s, Stanley Prusiner of the University of California (UC), San Francisco, proposed that proteins could be the infectious agent. It was a radical notion: All infectious agents known at the time contained DNA or RNA, the genetic blueprints for replication. But Prusiner proposed that infectious proteins, or prions, spread disease not by replicating themselves but by encouraging other proteins to undergo a conformational change. He won the 1997 Nobel Prize (some thought prematurely) for work supporting the prion hypothesis (Science, 10 October 1997, p. 214).
Prusiner's theory explained the kuru puzzle, but both Gajdusek and Prusiner were interested in applying the idea to a variety of other disorders. After all, autopsy studies commonly found suspicious clumps of protein in the brains of people who died of Alzheimer's, Parkinson's, and other neurodegenerative diseases. As early as the 1960s, Gajdusek tried injecting extracts of brain tissue from Alzheimer's patients into monkeys and chimps. But these efforts, and later attempts by other researchers, yielded inconsistent results.
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作者:admin@医学,生命科学 2011-02-24 12:48
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