Proteins Promote Heart Pangs

If you can remember the film Eternal Sunshine of the Spotless Mind, you may be pleased to hear that protein clusters in your brain may well account for this recall, but also for painful memories too, such as those attached to your last breakup.

Just two weeks before Valentine’s Day, Kausik Si and colleagues presented their results on the process of long-term memory formation, in the journal Cell. Their goal was to discover something new about the molecular composition of synaptic sites. Synaptic sites are communication points between neurons, and hence are of tremendous interest to brain scientists.

Previous experimental findings have already shown the relevance of clusters of the protein Orb2, a type of cytoplasmic polyadenylation element binding (CPEB) protein, in long-term memory formation. It is suggested that Orb2, in a clustered form called amyloid-like oligomer, achieves this by marking relevant synaptic sites during brain activity. Si and colleagues believe that such synaptic marks act as labels for brain activity as they only accumulate when there is synaptic activity.

“We found that these Orb2 oligomers become more numerous in neurons whose synapses are stimulated, and that this increase in oligomers happens near synapses,” says lead author Amitabha Majumdar, a postdoctoral researcher in Si’s lab.

Their results suggest that the majority of simple Orb2 is present in neuronal cell bodies, whereas clusters of Orb2 occur in the synaptic region. There is one important difference between simple and clustered forms of Orb2. The latter seems to be much more stable, bearing the potential to remain and self-renew for decades, hence contributing to long-term memory maintenance.

Not surprisingly, these results come from researchers affiliated with Eric Kandel, the Nobel Prize winning scientist who pioneered work on memory formation in the sea snail Aplysia. But for this study the researchers at the Stowers Institute for Medical Research turned to the fruit fly Drosophila to probe their theory.

The group used fly mutants in the Orb2A form, which is the Orb2 sub-type necessary for amyloid-like oligomerisation. In the experiments, flies lacking this type failed to stabilise memory beyond 48 hours. These results support the idea that amyloid-like oligomer clusters in neurons are critical for the persistence of long-term memory.

 “Self-sustaining populations of oligomers located at synapses may be the key to the long-term synaptic changes that underlie memory; in fact, our finding hints that oligomers play a wider role in the brain than has been thought,” says Si.

What may be most intriguing is what these amyloid-like oligomers protein clusters resemble. Protein formations of this type have classically been associated with neurodegenerative and prion diseases. In humans, however, the potential role of protein clusters – similar to Orb2 – for long-term memory remains to be established.

Scientists will continue digging deeper, allowing us to keep some memories by stacking up proteins, but keep the level lower for others, just to relieve the pain of the heartbroken. So enjoy it while it lasts. Happy Valentine’s Day.