Could They All Be Prion Diseases?

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Science  04 Dec 2009:
Vol. 326, Issue 5958, pp. 1337-1339
DOI: 10.1126/science.326.5958.1337

Recent studies have renewed interest in the idea that many neurodegenerative diseases may involve prionlike mechanisms.

Suspicious activity.

Peptide aggregates (yellow) similar to those involved in Huntington's disease display prionlike behavior.


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.

Disease can develop decades after exposure to prions in humans, and researchers had to wait years to see whether experiments in primates had any effect, says Walker. Enter the transgenic mouse: In a study published in 2000 in The Journal of Neuroscience, Walker and colleagues injected extracts from the brains of Alzheimer's patients into genetically engineered mice susceptible to the disease (normal mice are not susceptible). They injected one side of the brain in each animal. Within a few months, the mice developed widespread plaques made up of β-amyloid peptide, a hallmark of Alzheimer's disease, on the injected side of the brain. That indicated that something in the brain extracts can seed plaque formation, although whether the seed is β-amyloid peptide itself remained unclear.

More recent work led by Walker and Mathias Jucker at the University of Tübingen in Germany bolsters the case that β-amyloid is the culprit. In one experiment, the researchers found that brain extracts treated with antibodies to remove β-amyloid did not seed aggregation of β-amyloid when injected into mice (Science, 22 September 2006, p. 1781). And in the 4 August issue of the Proceedings of the National Academy of Sciences (PNAS), they reported that stainless steel wires coated with brain extract and then heated to kill microbes still caused β-amyloid deposits to form when implanted into the brains of mice. After 6 months, deposits had spread to neighboring brain regions. To Walker and others, such findings suggest that β-amyloid can induce deposits to form and spread through the brain—much as prions do. Walker says his group is working to create synthetic β-amyloid for a more def initive experiment: If a synthetic peptide can seed plaques, that should rule out the possibility that a microbe or some other factor in the brain extracts is to blame.

Early clues.

Studies by Daniel Carleton Gajdusek (left) with the Fore people led to early clues about prion diseases.


Other researchers have been finding similar hints of prionlike behavior in other proteins associated with neurodegenerative disorders. Diamond and colleagues have found that aggregates of misfolded tau, a protein that forms pathological tangles in the brains of people with Alzheimer's disease and frontotemporal dementia, can be taken up by cultured mouse cells. Then, once inside the cells, the misfolded tau appears to encourage normally folded tau to misfold and aggregate, they reported 8 May in The Journal of Biological Chemistry. In July, European researchers reported similar findings in vivo: Injecting brain extracts containing misfolded tau into the brains of mice triggered tau misfolding and aggregation that spread from the injection site to nearby brain regions, they reported in Nature Cell Biology.

Another suspect protein, α-synuclein, the main component of the “Lewy bodies” found in the brains of people with Parkinson's disease and certain types of dementia, also appears to propagate from cell to cell. In the 4 August issue of PNAS, researchers led by Eliezer Masliah of UC San Diego and Seung-Jae Lee of Konkuk University in Seoul reported that rogue aggregates of α-synuclein can pass from cell to cell and spur the formation of Lewy body–like aggregates in cultured human neurons. Experiments with cultured rat and mouse cells, reported in the same paper, suggested that α-synuclein triggers cell death in neurons and neural stem cells. “Cells that take it up form new aggregates, and they get sick and eventually die,” Masliah says.

If α-synuclein spreads from neuron to neuron in the intact human brain, that might explain findings from two research groups that reported last year that fetal cells transplanted into the brains of Parkinson's patients contained deposits of α-synuclein—something that's unheard of in such young cells, the oldest of which had survived for 16 years before the patient died. (A third team found no pathology in transplanted cells.) The findings surprised many researchers who had assumed that deposits build up inside cells over many decades and don't jump from cell to cell. Cell-to-cell transmission of α-synuclein wouldn't necessarily doom stem cell therapies for Parkinson's disease, but it may present yet another obstacle, Masliah says. “We'd like to engineer those fetal cells to be resistant to the aggregates,” he says. One possibility, he suggests, would be to engineer them to overexpress enzymes that can break down aggregates.

Tangled up.

Aggregates of tau protein (green specks) can transfer from one cultured cell to another.


Is it contagious?

The list goes on. Misfolded huntingtin protein, the culprit in Huntington's disease, can find its way from the extracellular fluid to the inside of cultured cells and trigger aggregation, according to a report by Stanford University cell biologist Ron Kopito and colleagues in the February issue of Nature Cell Biology. And at the Alzforum seminar, Neil Cashman of the University of British Columbia, Vancouver, in Canada described unpublished findings from his group that hint at prionlike behavior in SOD1, a protein thought to be central to neurodegeneration in amyotrophic lateral sclerosis. “We're getting a lot of hints from a lot of diseases,” Kopito says. “Together, it adds up to an emerging picture that deserves some pretty close attention.”

A spreading problem.

Aggregates of α-synuclein (red, left; orange in merged panel on right) can pass between mouse neural stem cells (green, middle).


These recent studies “expand the prion concept to other proteins … [and] show that under certain conditions the process of protein aggregation can be transmissible” from cell to cell, says Claudio Soto, a molecular biologist who studies neurodegenerative disease at the University of Texas Medical School at Houston. “What remains to be seen is whether or not this occurs in real life,” Soto says.

So far there's virtually no evidence that proteins other than prions can transmit disease from one individual to another, notes Adriano Aguzzi, a prion researcher at the University Hospital of Zurich in Switzerland. One exception, Aguzzi says, may be amyloid A amyloidosis, a protein misfolding disorder that affects the spleen, liver, and other organs. Japanese researchers reported in PNAS in 2008 that misfolded amyloid A can be transmitted from one captive cheetah to another via feces. (The disease is a major cause of illness and death in these endangered cats.) A 2007 paper in PNAS suggested that foie gras prepared from duck or goose liver can transmit amyloidosis when fed to mice.

Most researchers say it's unlikely that diseases like Alzheimer's and Parkinson's are contagious in the usual sense of the word. “I think what's special about prion diseases is that prions are indestructible,” says Walker. “There's practically nothing you can do to get rid of them within the realm of what we consider normal sterilization.” Most protein aggregates are more fragile, which may limit their ability to jump from one person (or animal) to another. All the same, Walker says the issue merits closer study. His experiments with the stainless steel wires, he notes, suggest at least a theoretical possibility that surgical instruments could transmit the disease.

Window of opportunity

Even if most neurodegenerative diseases don't spread from individual to individual like true prion diseases do, the possibility that they may spread from cell to cell in an analogous way opens up new options for treating them, say some researchers. If aggregates of tau jump from cell to cell to spread disease instead of building up slowly inside cells, for example, that presents an opportunity to cut them off with antibodies or other molecules that can't get inside cells, says Diamond. His group has been designing antibodies that specifically target misfolded forms of tau. Cashman's group has been taking a similar approach for SOD1. Both presented promising preliminary results from animal experiments at the Alzforum seminar.

Another approach is to use small molecules designed to latch on to specific parts of a protein and prevent it from misfolding, says Jeffrey Kelly, a biochemist at The Scripps Research Institute in San Diego, California. In July, FoldRx Pharmaceuticals, a company Kelly cofounded, announced encouraging results from a phase II/III clinical trial of a compound that prevents protein misfolding and aggregation in people with a rare but fatal disease called transthyretin amyloid polyneuropathy. The disease affects the peripheral nerves, causing loss of function in the hands and feet, before spreading to the autonomic nervous system, which regulates digestion and other essential functions. Untreated, the disease causes drastic weight loss, but patients who took the drug for 18 months reversed course and started gaining weight, Kelly says. That suggests that the drug slows the disease's impact on the autonomic nervous system, Kelly says. “We're pretty excited about this, and I think it will energize efforts on other amyloid diseases that focus on preventing this process.”

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