Are memories formed by prions?

(Second of two parts)

In an article that appeared recently in Biosciences Hypotheses, we proposed that electrical activity at the synapse induces the surrounding prion molecules to aggregate. The aggregates serve to hold together the synaptic connection between neurons which are interacting at the instant the sensory stimulus is received. The set of neurons connected in this manner then forms the neuronal circuit which is associated with the particular stimulus. We proposed that the stronger the electrical activity, the greater will be the aggregations. Long-lasting memory will result from traumatic, or exciting, experiences. Further, the aggregations will be maintained, or reinforced, by repeated stimulation of the same set of neurons. Memory loss will occur when those aggregates dissolve. 

The effect of electric field on protein structure is well known and pulsed electric fields are actually used to inactivate harmful germs in food. Pulsed electric fields have been observed to cause protein unfolding, self-aggregation, and even changes in secondary structure. The electric fields, to which the proteins present in a neural synapse are subjected, are of comparable strength to those used in food processing.

An electrical impulse arriving at the synapse could then significantly affect the structure of proteins present in the synaptic cleft, especially those which are susceptible to structural deformation like prions. Thus, we believe that a consequence of neuronal electrical activity is the destabilization of the prion structure and self-aggregation, leading to a stronger synaptic connection and, thereby, the formation of neuronal circuits.

It is known that susceptibility to neurodegenerative disease is associated with mutations in the prion gene. For example, the M129 variant (the prion variant which has the amino acid methionine at position 129) is associated with susceptibility to Creutzfeld-Jacob Disease and this variant has been shown to oligomerize more rapidly than the V129 variant (the variant which has valine at position 129). We predict that the variants which are the most susceptible to neurodegenerative disease are those which aggregate the most in response to electrical impulses.

Surprisingly, the M129 variant is found to be common in the human population. The prevalence of this variant in the Fore tribesman, who acquire the prion disease, kuru, through cannibalism, has led to the conclusion that cannibalism may have been a common occurrence in human history. Here, also, we disagree.

We propose instead that the M129 variant, because of its greater tendency to aggregate, is linked to long-lasting memory, while the less-aggregating V129 variant is linked to poor memory. Homozygosity in either M129 or V129 thus presents an evolutionary disadvantage. Heterozygosity, on the other hand, leads to good memory and diminished susceptibility to fatal disease. 

This linkage is completely analogous to the situation found in sickle cell anemia. Homozygosity in the hemoglobin variant that causes sickle cell anemia often results in early death, but provides protection against malaria; homozygosity in the normal variant does not lead to sickle cell anemia, but does not provide protection against malaria; heterozygosity provides protection against malaria without causing sickle cell anemia. Thus, the sickle cell mutation is found to be common in areas of Africa and the Mediterranean where malaria is prevalent.

Prion sequences are highly conserved among mammals (there is 93 percent sequence identity in the 209 residues of the mature prion molecules of humans and sheep, for example) and the molecule is found in other vertebrates, as well as in lower animals, yeast and prokaryotes. It has to have an important function. Prions may be the molecules which allow us to remember - and to forget.

“Prion” may not be such a bad word after all.

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Eduardo A. Padlan is a corresponding member of the NAST and is an adjunct professor in the Marine Science Institute, College of Science, University of the Philippines Diliman. Gisela P. Padilla-Concepcion is an academician of the NAST and is a professor in the UP Marine Science Institute. They can be reached at [email protected] and [email protected], respectively.