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Evidence that prions have been conserved over long periods of time suggests to Jonathan Weissman that some proteins can form beneficial prions.
In the intervening years, a variety of proteins with primitive self-sustaining properties have been found in yeast, fungi and bacteria, snails, flies, turtles, frogs, birds, mice, and other mammals, including cattle, sheep, deer, elk, and people. The functions of these prions are far more diverse and complex than anyone imagined.
Prions are proteins that have converted from a normal configuration to a “misfolded,” self-perpetuating form that reproduces even though it lacks a genetic blueprint like DNA or RNA. Like one bad apple spoiling the barrel, the prion sets off a cascade, converting other proteins of the same kind from which it was formed into prions as well.
To be sure, some prions are nothing but bad news. That first one, termed PrPSc by Prusiner, forms toxic amyloids, abnormal proteins that aggregate to form tough, fibrous deposits in cells. Amyloids spread through the brain and spinal cord, decimating nerve cells in animals and humans.
A string of recent findings, however, shows that some prions can serve beneficial functions—among them: helping maintain long-term memories in snails, mice, and fruit flies; fast-forwarding evolution in yeast to equip them with survival traits; aiding synthesis of the pigment melanin in mammals; forming biofilms that give adhesive properties to bacteria; and storing hormones inside endocrine cells.
“The disease prions are just a minor idiosyncrasy,” says HHMI investigator Susan Lindquist, a leading researcher on protein folding and prions at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology. “Prions are a really deeply rooted part of normal biology.”
She developed this silver-lining view of prions back when most scientists saw nothing but their destructive side. In a review written in 1997, Lindquist wrote: “My contention is that yeast and mammalian prions are not oddities in a biological freak show, but actors in a larger production now playing in a theater near you.”
That prediction is being borne out by a stream of discoveries from her Whitehead laboratory and others in the United States and abroad. “The real excitement now is to determine how widespread this biology is,” Lindquist says.
The first hint that prions might be advantageous in multicellular organisms came in 2003 in a series of studies in the giant marine snail Aplysia californica. A major question in brain research is how memories are stored. Research in Aplysia had shown that memories are stored at specific nerve synapses that undergo long-term strengthening that lasts as long as the memory lasts. In the first of two papers published in Cell in 2003, HHMI investigator and neuroscientist Eric Kandel at Columbia University, and his former postdoc, Kausik Si, now at the Stowers Institute for Medical Research, found that the long-term maintenance of this process at nerve synapses requires continuous production of proteins, which is regulated by a protein called CPEB.
But how did CPEB keep this process going? Si noticed that one end of CPEB resembles the prion domain found in yeast prions. He suggested that the protein could convert to a self-perpetuating form that was distinctively prion-like. He and Kandel wondered if, when stimulated repeatedly (as in learning), the CPEB in synapses could become a self-sustaining protein that spurs the ongoing translation of messenger RNA (mRNA) into memory.
“In principle, this could be how you remember things for the rest of your life,” says Kandel.
To test this idea Kandel and Si joined forces with Lindquist. In the second 2003 Cell paper, they observed that CPEB proteins from the Aplysia, when inserted into yeast, formed self-perpetuating units. In a follow-up paper in Cell in February 2010, Si and Kandel showed the same in Aplysia's own sensory neurons: CPEB acts like a self-sustaining prion and the prion form is essential for maintaining the synaptic strengthening that forms a memory.
Photo: Lenny Gonzalez