Prion diseases are among the most frightening known to medicine. They can burn through their victims’ brains in a matter of months, leaving the organs light, spongy, and dead. The agent of these diseases is now thought to be an abnormal small aggregate, or “oligomer,” of the natural neuronal protein PrP. This oligomer is somehow toxic to neurons, but arguably its worst feature is its ability to self-propagate. Much like DNA, it acts as a template for its own reproduction, taking free copies of PrP in its vicinity and fashioning new oligomers from them. These go on to convert other free copies of PrP into toxic oligomers, and so on in a chain reaction that spreads throughout the brain.
Other protein aggregates have this prion-like ability to self-replicate, including amyloid-beta and tau oligomers in Alzheimer’s disease, alpha-synuclein oligomers in Parkinson’s disease, and huntingtin oligomers in Huntington’s disease. Scientists now suspect that self-replicating aggregates drive most cases of neurodegenerative disease. Yet there is evidence that prion-like aggregates in certain cases are non-toxic and even play a positive role, by allowing organisms to create very long-term changes in function—including the synaptic changes in neurons that are the basis for our long-term memory.
“There’s been so much talk about how prions are bad, that there’s just kind of a prejudice against them,” says Susan Lindquist, a biology professor and prion researcher at the Massachussetts Institute of Technology. “People need to open their minds a bit.”
“These self-templating aggregates may represent an ancient form of molecular memory,” says Yury Chernoff, a biology professor at the Georgia Institute of Technology.
The “prion switch”
Researchers over the past decade or so have identified a number of self-replicating protein aggregates in yeast that seem to work as “good prions.” In such cases, the protein’s aggregation puts it into an alternate functional state. The yeast Sup35 protein, for example, controls a key step in the translation of genes into proteins within cells. Lindquist and colleagues have found evidence that when its host cell is stressed, Sup35 is produced at higher concentrations, triggering a rapid switch to an aggregated, prion-like state. In this state it lacks some of its normal control over the protein-translation process, and thus the cell produces a greater amount of variation in its proteins. Lindquist thinks that this may be an evolved strategy to give the organism greater versatility at times of environmental stress.
This “prion switch,” as she calls it, lasts much longer than other, simpler chemical modifications of proteins. One reason is that prion-like aggregates have molecular structures (also called amyloid structures) that make them chemically sturdier than single copies of their constituent proteins. The PrP-based aggregates that transmit prion diseases are an extreme example of this: They remain transmissible even when exposed to ordinary cooking or detergents, and thus can spread via the food chain.
Do prions underlie long-term memory?
There may be functional prion-like aggregates in humans too. “It seems impossible that they are confined to yeast and other fungi,” says Chernoff. Researchers don’t have definitive evidence of “good prions” that work alongside other proteins in human cells, but there is at least one likely candidate: a prion-like aggregate formed from a protein called CPEB (cytoplasmic polyadenylation element binding), which works in neurons to stabilize long term memories.
In 2003, Kausik Si, then a graduate student in the Columbia University neuroscience laboratory of Eric Kandel, published findings with Kandel and Lindquist that strongly pointed to this possibility. (Kandel is a vice president of the Dana Alliance for Brain Initiatives.) Si had been working with Aplysia californica, a sea slug favored for research because its neurons are large and easily studied. He found evidence that an Aplysia neuronal CPEB protein is crucial for maintaining the synapse alterations that underlie long-term memory. CPEB proteins are found in many species including mammals, so the finding is likely to be relevant for humans. At the same time, to his surprise, Si found that this neuronal variant of CPEB has a peculiar segment at one end, resembling the flexible, self-sticky segments commonly seen on PrP and other aggregate-forming proteins. “We hypothesize”—Si, Lindquist, and Kandel wrote at the time—“that conversion of CPEB to a prion-like state in stimulated synapses helps to maintain long-term synaptic changes associated with memory storage.”
More recent work by Si—now in his own lab at the Stowers Institute in Kansas City, Missouri—and by Kandel and Lindquist and their labs, has added weight to this idea. For example, Si and colleagues confirmed in a study published on Jan. 26 that the CPEB-like protein that stabilizes memories in fruit flies does its work not in the single-copy form, but only when it has formed oligomeric aggregates.
CPEBs normally act as regulators on the production of other proteins within cells. In the case of neuronal CPEB, says Si, the ordinary, single-copy “monomer” form seems to bind to genetic material in a way that suppresses the production of synapse-building proteins. By contrast, the oligomer form binds more weakly or somehow differently, so that the brakes stay off, synapse-building proteins stay abundant, and—according to Si’s current model—synapses stay strong. This synapse-maintaining “switch” process also is nearly permanent: “The oligomers are a hardier species in the cell because they’re amyloids, plus they are constantly maintaining their own population by converting monomers,” Si says.
What distinguishes good prions from bad ones?
The finding that a prion-like mechanism underlies something as fundamental as long-term memory would be astonishing enough. But “good” prion-like aggregates may also play a crucial role in helping scientists understand the bad ones and the major diseases they cause.
The “million-dollar question,” says Si, is why so-called good prions fail to cause harm, whereas bad ones are toxic. Si and his colleagues have found that fruit-fly CPEB oligomers don’t harm neurons even when expressed in high amounts—“but if we do the identical experiment with huntingtin protein, it kills the cells within a day,” Si says.
One possibility is that bad prions stabilize in structures that are toxic, whereas good prions don’t. Lindquist and her colleagues have found, for example, that a solution of yeast Sup35 can react with antibodies that are specific for common structures on toxic oligomers such as amyloid beta oligomers – which suggests that some of the Sup35 exists in toxic form. She thinks that in such cases, Sup35 aggregates can exist in toxic shapes, but only briefly, before moving on to form non-toxic structures. “We really do think that there’s a strong relationship between the functional prions and the very toxic species,” Lindquist says. “It’s that the functional ones have evolved to move very quickly out of that [toxic] space.” Researchers already have established that for disease-linked aggregates, such as amyloid beta aggregates, the oligomer-sized aggregates are more likely to be toxic, whereas the larger amyloid fibrils are relatively harmless.
Another important question is whether good prions—especially as the brain’s protein-control mechanisms weaken with age—can act as seeds to trigger the aggregation of bad ones. “There’s a tremendous amount of cross-seeding between yeast prions; that happens all the time,” Lindquist says. “So I wouldn’t be at all surprised if cross-seeding could happen in the human brain too.” Indeed, some scientists suspect that the most destructive and irreversible stage of Alzheimer’s disease occurs when toxic amyloid beta oligomers somehow directly or indirectly seed the formation of toxic tau protein oligomers. Chernoff’s lab has shown that, at least in the lab dish, an apparent cross-seeding can happen between a bad human prion-like protein—a fragment of mutant huntingtin—and the yeast prion Sup35. Thus, in principle, a functional aggregate such as CPEB, which keeps memories, could trigger the aggregation of proteins such as amyloid beta and tau, which destroy memories.
“It’s a possibility that we should keep in mind,” says Chernoff. “And it’s one reason why I’m working in this field of research—there are just so many implications for normal biology and disease.”