Actin pulls upon and stabilizes soluble cytoplasmic polyadenylation element binding proteins into longer, insoluble prion-like fibers, a process believed to be key to stabilizing long-term memories. Rice University researchers simulated the force (F) applied by actin through computer models that predict how proteins are likely to find their least-energetic (and most stable) states. Credit: Mingchen Chen/Rice University
Thank the little “muscles” in your neurons for allowing you to remember where you live, what your friends and family look like and a lot more. New research at Rice University suggests actin filaments that control the shape of neuron cells may also be the key to the molecular machinery that forms and stores long-term memories. The theory is based on simulations that analyze the energy landscapes of the proteins involved.
Wolynes and his colleagues are pioneers in the development of an energy landscape theory for proteins, which enables them to build computer models of proteins to predict how they will fold. These molecular-dynamics simulations employ the principle of minimal frustration by which proteins find their most stable folded forms.
For long-term memories, stability is desirable. Wolynes et al determined the path to encoding memories may lie in the way actin filaments – the “muscle” part of the cytoskeleton in every eukaryotic cell – pull upon and stabilize soluble cytoplasmic polyadenylation element binding proteins (CPEB) into longer, insoluble prion-like fibers.
Prions are proteins that, when they misfold, are thought to become self-propagating and cause infectious diseases like Creutzfeldt-Jakob disease and other disorders. But their very existence and the transitions known to take place in synapses suggest properly folded prions must have a biological function. These transitions were the focus of their study.
CPEB proteins, when made in cells, first bind a few at a time in oligomers, which are coiled alpha helices. The intrinsic energy landscapes of these oligomers allow mechanical forces provided by actin to prompt a transition into longer beta strands that are much more stable. These now-stable fibers are thought to aggregate and encode memories in neurons’ synaptic regions.
“Short-term memories that last less than an hour or so seem to be done through the electrical and direct biochemical circuitry. Forming these memories doesn’t seem to require creating new protein,” Wolynes said. Researchers who conducted experiments with sea slugs poisoned to prevent them from synthesizing proteins seemed to confirm that, he said. “They found these snails were able to memorize things for short periods of time but not for periods of hours when protein synthesis was stopped.”
The mechanical force provided by actin can restructure CPEB into a longer fiber with new hydrogen bonds between the coils. Wolynes said that the restructuring not only forces CPEB to a lower-energy, prion-like state, but also allows the prion to bind an RNA sequence that otherwise prevents more actin from being synthesized. The resulting feedback loop further stabilizes the memory.
“We still don’t understand the beginning of the process, how you go from short-term to long-term memory,” he said. “But we can now see that actin starts to form in a particular location in response to electrical signals. The actin then takes any CPEB oligomers that are around and activates them, which makes more actin and causes the formation of a self-replicating prion of the CPEB. That prion aggregates until it stops, changing the structure of the synapse in a way that should last for a very long period of time, perhaps decades.”
Wolynes considers the new study a beachhead to launch others to determine the entire process of how memories form, as well as the implications for diseases like Alzheimer’s and Parkinson’s that involve protein aggregation. http://news.rice.edu/2016/04/18/thanks-actin-for-the-memories-2/
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