Mad Cow Disease and Memory Maintenance Have Something in Common
And no, its not that they both start with the letter M.
A hunt for a “memory molecule,” a protein responsible for latching onto our experiences and lodging them somewhere between the synapses in our brain, has dominated the field of neurobiology for nearly 2 decades. Much light has been shed on an enzyme called protein kinase C (PKC) — during memory formation, PKC becomes constitutively active, meaning that it gains the ability to limitlessly phosphorylate substrates at neural synapses. When drug inhibitors of this hyper-active PKC were tested in mice, researchers found that mice could no longer form long-term memories for spatial navigation or sensory discrimination-based tasks. But of course, like any molecular mechanism, PKC is only part of a very complicated story. In fact, when a PKC knockout mouse (i.e. a mouse who’s genome no longer encodes PKC) was finally engineered and battered with memory tasks, its performance was, to the surprise of scientists, completely normal. What does this mean? A compensatory kinase might be taking over for the loss of PKC in these mutants, however, another hypothesis is rapidly gaining popularity: prions.
Now, if you don’t remember exactly what a prion is, you’ll still probably remember that whatever they are, they’re not supposed to be good. Prions are essentially self-propagating, pathogenic molecules that seem to be composed of a modified protein (PrPSc), and yes, they are very bad. PrPSc is an isoform of the normal membrane protein PrP, and it orchestrates its dirty work much like zombies do it on The Walking Dead: PrPSc not only forms toxic aggregates within cells, but it converts the remaining “normal” PrP into infectious PrPSc. This mechanism is ultimately responsible for pathologies like scrapie, kuru, fatal familial insomnia, and the infamous “Mad Cow Disease” (bovine spongiform encephalopathy).
Amidst all this bad stuff, when we’re making memories, prions might actually be pretty useful. The cytoplasmic polyadenylation binding protein (CPEB), a molecular modulator of mRNA translation, has now been claimed to represent a new class of “functional prions” in invertebrate and vertebrate genomes. Work from the labs of Kausik Si and Nobel laureate Eric Kandel suggest that during memory formation, synapse-specific signals can activate CPEB, which consequently embarks on a prion-like trajectory of self-maintenance and multimerization. In this functional prion state, CPEB aggregates coordinate the translation of many synapse-specific mRNAs that contribute to the strengthening of memory-relevant synapses. Refreshingly, this model for regulation and maintenance of local protein synthesis makes a lot of sense: normal synaptic proteins undergo constant turnover— a prion-like aggregate can replenish its own supply, essentially persisting as long as our oldest memories.
This is the first evidence of a prionic mechanism in the brain, and while still in its initial stages of investigation, may open the door to the discovery of more functional prions within the human genome.
