Prion-like Proteins Maintain Long-term Memories

More evidence of a system in the brain that maintains memories for long periods of time has been found by Columbia University Medical Center researchers. Intriguingly, it functions similar to the mechanisms that cause mad cow disease, kuru, Creutzfeld-Jakob disease, and other degenerative brain diseases.

In the work, Dr. Eric Kandel shows how prion-like proteins play a key role in maintaining long-term memories in mice, and probably other mammals. The lead authors of the four papers are Luana Fioriti, Joseph Stephan, Luca Colnaghi and Bettina Drisaldi.

When long-term memories are made in our brains, new connections are made between neurons to store the memory.

But the connections must be maintained for a memory to persist, or else they will degrade and the memory will disappear within days. Many researchers have sought molecules that could maintain long-term memory, but their identity has remained elusive.

These memory molecules are a normal version of prion proteins, according to research led by Nobel laureate Eric Kandel, MD, who is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC.

Protein Infectious Particles

Prions (protein infectious particles) are a distinct class of proteins. Unlike other proteins, they are both able to self-propagate and also to persuade other proteins to take on their alternative shape.

When prions form in a cell, in this case a neuron cell, they cause damage by grouping together in sticky aggregates that disrupt cellular processes. Prion aggregates are highly stable and accumulate in infected tissue, causing tissue damage and cell death.

The dying cell releases the prion proteins, which are then taken up by other cells, and are thus considered infectious.

These abnormal proteins are known to cause mad cow disease (bovine spongiform encephalopathy). They also have been linked to a variety of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s.

Functional Prion Proteins

By contrast, functional prion proteins are able to play a physiological role in the cell and do not contribute to disease.

Kausik Si and Dr. Kandel first identified functional prions in the giant sea slug (Aplysia) and found they contribute to the maintenance of memory storage. More recently, the Kandel laboratory searched for and found a similar protein in mice, called CPEB3.

In one of many experiments described in the paper by Luana Fioriti, the researchers challenged mice to repeatedly navigate a maze, allowing the animals to create a long-term memory. But when the researchers knocked out the animal’s CPEB3 gene two weeks after the memory was made, the memory disappeared.

The researchers discovered next how CPEB3 works inside the neurons to maintain long-term memories.

“Like disease-causing prions, functional prions come in two varieties, a soluble form and a form that creates aggregates,” said. Kandel. “When we learn something and form long-term memories, new synaptic connections are made, the soluble prions in those synapses are converted into aggregated prions. The aggregated prions turn on protein synthesis necessary to maintain the memory.”

As long as these aggregates are present, Kandel says, long-term memories persist. Prion aggregates renew themselves by continually recruiting newly made soluble prions into the aggregates.

“This ongoing maintenance is crucial,” said Dr. Kandel. “It’s how you remember, for example, your first love for the rest of your life.”

A similar protein exists in humans, suggesting that the same mechanism is at work in the human brain, but more research is needed.

Fioriti L, Myers C, Huang YY, Li X, Stephan JS, Trifilieff P, Colnaghi L, Kosmidis S, Drisaldi B, Pavlopoulos E, Kandel ER
The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3
Neuron 2015 Jun 17;86(6):1433-48. doi: 10.1016/j.neuron.2015.05.021

Eric Kandel, Luana Fioriti, Cory Myers, Yan-You Huang, Xiang Li, Joseph Stephan, Pierre Trifilieff, Luca Colnaghi, Stelios Kosmidis, Bettina Drisaldi, and Elias Pavlopoulos
SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3
Cell Reports Volume 11, Issue 11, p1694–1702, 23 June 2015 DOI: http://dx.doi.org/10.1016/j.celrep.2015.04.061

Kandel et al
The CPEB3 Protein Is a Functional Prion that Interacts with the Actin Cytoskeleton
Cell Reports, Vol. 11, Issue 11, p1772–1785 DOI: http://dx.doi.org/10.1016/j.celrep.2015.04.060

Ferdinando Fiumara, Priyamvada Rajasethupathy, Igor Antonov, Stylianos Kosmidis, Wayne S. Sossin, Eric R. Kandel
MicroRNA-22 Gates Long-Term Heterosynaptic Plasticity in Aplysia through Presynaptic Regulation of CPEB and Downstream Targets
Cell Reports Volume 11, Issue 12, p1866–1875, 30 June 2015 DOI: http://dx.doi.org/10.1016/j.celrep.2015.05.034

Illustration: Memories are stored for the long-term with the help of prion-like proteins called CPEB. CPEB prions aggregate and maintain synapses that recorded the memory [“spines” in the bottom image]. When CPEB prions are not present or are inactivated, the synapses collapse and the memory fades [see upper image]. Credit: Lab of David Sulzer, Ph.D., Columbia University Medical Center

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