Study hints at vital job for two-faced proteins.
Mystery proteins called prions, which can flip between two different shapes, might help in laying down memories, according to US researchers. The finding hints at an entirely new set of roles for the proteins.
Prions are unusual in the protein world: when they adopt one of their guises, they can reproduce, converting other identical proteins into copies of themselves. Often such replicating prions are harmful - they clog up the brains of cattle with mad cow disease and patients with variant Creutzfeldt-Jakob disease (vCJD).
Now a team led by Eric Kandel at Columbia University in New York has found that a prion-like protein called CPEB may help nerve cells store memories. A transient electrical signal in the brain might flip CPEB into its prion form, the researchers suggest, helping to create a permanent memory trace.
The finding raises the prospect that other prion-like proteins could serve all kinds of essential biological functions. "I think there's tons of them," says team member and prion expert Susan Lindquist of the Whitehead Institute in Cambridge, Massachusetts.
Prions that switch genes on and off in one cell, say, could be passed onto another, Lindquist suggests - a form of inheritance that bypasses DNA. "I think it's an aspect of protein biology that has probably existed since the beginning of time," she says.
CPEB is a sea-slug protein that dwells at the connections - or synapses - between nerve cells. When active, CPEB ramps up production of other proteins, allowing the nerve cell to build and maintain new, stronger links with a neighbouring neuron1. This process is the basis of memories.
I think it's an aspect of protein biology that has probably existed since the beginning of time Susan Lindquist , Whitehead Institute
Kandel and his colleagues investigated how CPEB works by inserting it into yeast cells. They found that CPEB was switching into a prion-like form that replicates and is inherited by other cells2. "It acts exactly like a prion," Kandel says.
The findings led them to develop a model of how memories are formed. An experience sends an electrical signal zapping down a nerve cell to trigger certain synapses. This could switch CPEB into its active prion form, Kandel suggests.
The prion proteins replicate and, together, strengthen connections with next-door neurons. The mechanism "is intriguing", says Giuseppe Legname, who studies prions at the University of California, San Francisco.
Legname points out that the model is largely unproven - the team has not yet shown that CPEB actually works as a prion in sea-slugs, let alone humans. But humans and other mammals carry a version of CPEB, and "it will be very interesting to see what they do", says Legname.
Si, K. et al.A neuronal isoform of CPEB regulates local protein synthesis and stablizes synapse-specific long-term facilitation in Aplysia. Cell, 115, 879 - 891, (2003).
Si,K., Lindquist, S. & Kandel, E.R. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell, 115, 879 - 891, (2003)
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Pearson, H. Prion proteins may store memories. Nature (2003). https://doi.org/10.1038/news031229-2