Choose Your Own (Prion) Adventure: Memory or Madness

In the early ‘80’s ranchers in Great Britain began to notice strange behaviors in their cows.  What began with increased aggression and an inability to walk turned into a strange and deadly neurological disease that we now know to be a spongiform encephalopathy or mad cow disease.  Despite the fact that only four confirmed cases of variant Creutzfeldt-Jacob disease (the human form of mad cow disease) have been observed in the United States, it is up there with shark attacks and lightning strikes as a rare event that terrifies the population.  According to the journal of Emerging Infectious Diseases, Creutzfeldt-Jacob results from abnormal conformations of prions – rogue proteins that form aggregates in the brain and spinal cord.  The leading hypothesis regarding the origin of this disease is that the ingestion of an abnormal prion protein from diseased meat causes a normal human prion protein to change shape and aggregate in between neurons.

In the context of this history, recent research from the laboratory of Nobel Prize winning scientist, Dr. Eric Kandel on a prion-like protein that plays a role in long-term memory is particularly interesting.  Why is it that a prion protein can play a deadly role in mad cow disease but also have an evolutionarily conserved function in forming memories?  In new research published in Neuron, the researchers were interested in exploring what happens in the brain when long-term memory is formed.  Long-term memory is different from short-term memory, as it requires gene transcription (new protein synthesis) and the growth of new synaptic connections (Dudai, 2002).  In invertebrates like the fruit fly model organism, it was found that memory is regulated by a prion-like protein called Orb2.  In mammals, this protein is called CPEB or cytoplasmic polyadenylation element binding protein.  If this gene is knocked out during development, could long-term memory be affected (Fioriti et al., 2015)?

In the first set of experiments, it was found that activation of long-term potentiation (LTP) increased the levels of the prion-like protein CPEB3 in the hippocampus.  LTP can be thought of as a persistent strengthening of synapses due to patterns of synaptic activity that increase signal transmission between two neurons.  Mice that engaged in a behavioral learning task also showed an increase in CPEB3 in the hippocampus.  In the aftermath of both LTP and hippocampal based learning, the CPEB3 protein aggregated in response to the stimulation.

To really test the role of CPEB3 in long-term memory, the researchers used clever genetic manipulations to knock out expression of the CPEB3 gene.  The N-terminus of the protein contains a prion domain; therefore, removing the 220 amino acids responsible for this protein should prevent mice from having normal long-term synaptic plasticity and long-term memory.  Indeed, this is exactly what they found!  This result indicates that the prion-domain of this protein is essential for hippocampal-based memory.  This research highlights a protein that aggregates in response to synaptic activity.  Interrupting the synthesis of this protein interfered with memory formation suggesting that a protein with a dangerous tendency to aggregate in mad cow disease also plays a crucial role in normal memory!

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References:

Dudai, Y. (2002). Molecular bases of long-term memories: a question of persistence. Current Opinion in Neurobiology, 12(2), 211–216.

Fioriti, L., Myers, C., Huang, Y.-Y., Li, X., Stephan, J. S., Trifilieff, P., et al. (2015). The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion- like Protein CPEB3. Neuron, 86(6), 1433–1448. http://doi.org/10.1016/j.neuron.2015.05.021

Images by Jooyeun Lee and from Dr. Luana Fioriti.