A symphony of proteins orchestrates small changes in nerve cell connectivity that regulate human memory. One of the key proteins is Arc that enables the nerve cells to grow and functions as a signal between them. Now researchers have mapped the structure of Arc and found that, confusingly, it resembles a protein that HIV uses to encapsulate itself. Arc also creates virus-like particles that can transmit information between nerve cells. The new knowledge improves our understanding of how nerve cells communicate and how this system might be used to create medicine that can be delivered better into the brain.
Brain cells work rapidly when we experience things or learn. Electrical and chemical signals are transmitted between cells, and synapse connections are created or destroyed. This is how we remember and forget again. The Arc protein plays a key role in adjusting memory and helps the brain’s neurons to grow. Arc can also change shape and function as an external signalling molecule. The researchers hope that they can use this property to understand how we remember and learn but also to develop medicine that can cross barriers in cells and the brain.
“To do this, we need to understand Arc’s somewhat peculiar behaviour better. In that process, we found that Arc is similar to the proteins used by HIV to form a protective shell – a capsid. Exactly how the gene encoding Arc was introduced into our DNA is still uncertain. What is certain, however, is that Arc originally stems from another organism. Subsequently repurposed, it has also become a key actor in our brains and in our ability to remember and learn,” says Simon Erlendsson, Assistant Professor, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom and Department of Biology, University of Copenhagen.
Long-term memory disappears
It is not just Arc’s similarity to HIV that makes it very special. The genetic template for most proteins is in or around the cell nucleus, whereas this template for Arc is transported all the way to the synapses through which the nerve cells communicate, which are often very far from the cell nucleus where they are formed. In this way, Arc is always available in the synapses and plays a crucial role in regulating the cytoskeleton that controls the shape and function of nerve cells.
“Arc provides a potentiation effect that promotes the growth of neurons when new contacts in the brain need to be created. Many RNA templates of Arc are therefore ready in the synapses, so that Arc can be produced at very short notice,” explains Simon Erlendsson.
When genes are translated into proteins, the cell first translates the genes’ DNA into messenger RNA molecules, which are then translated into proteins with the aid of ribosomes. Arc messenger RNA is translated directly into the synapses by a full arsenal of polyribosomal units.
“There is currently much focus on understanding how Arc plays such a pivotal role in the brain. If Arc is removed from the brain of rats, their long-term memory disappears because certain neurons and/or synapses are downregulated. Arc stimulates the creation and restructuring of the cytoskeleton and also interacts with many other proteins – especially with receptors stimulated by glutamate present on the cell surface of neurons,” says Simon Erlendsson.
Pathway for treating brain diseases
Glutamate is one of the most important neurotransmitters in our brain, and glutamate receptors therefore play an equally central role.
“Arc appears to redistribute the production of these receptors. Because the receptors are heavily recycled, strict regulation is important, and here Arc plays a very important role. But that is not all, because Arc is a fairly crazy protein in every way. It turns out that Arc can also interact with itself, forming virus-like capsids containing Arc messenger RNA. Incredibly, the Arc capsids can also travel from neuron to neuron, thus regulating networks of individual synapses or whole neurons,” explains Simon Erlendsson.
In particular, Arc’s ability to form capsids has especially increased the interest in understanding its structure. However, using and imitating these abilities may be possible without fully understanding its structure. Delivering medicine into the brain and into brain cells is usually extremely difficult, which makes it even harder to treat brain diseases.
“We wanted to understand Arc’s unique characteristics and therefore started to study Arc’s structure and capsids and how these change. During the process, we came across the rather surprising similarities to the group-specific antigen (gag) proteins from retroviruses such as HIV,” says Simon Erlendsson.
Neither fish nor fowl
In retroviruses, the gag protein also forms viral capsids that protect the viral DNA and other viral machinery from being degraded in the cells. Retroviruses spread from cell to cell through these protective capsids and are able to incorporate their viral DNA into the host that is infected. Retroviruses thus use the cells’ own machinery to multiply.
“Our high-resolution structure of the Arc capsids shows that they are similar in structure to retroviral and especially HIV capsids and that several key elements and functions are preserved between the Arc capsids and retroviruses. Arc has probably been incorporated into our DNA as a simpler and earlier type of retrovirus,” explains Simon Erlendsson.
By comparing the Arc DNA sequences from many organisms, researchers have been able to look back in time to identify the places in which these very unique proteins may have originated. However, although fish and fowl have no equivalents, the proteins can be found in the organisms we use to make beer.
“Yeast contains the Ty3 retrotransposon that also forms capsids and that the yeast uses to reorganize its DNA. Conversely, the Ty3 capsids cannot be transferred between cells. Our studies show that Ty3 is a common ancestor of both Arc and HIV. Arc was probably introduced into our DNA about 250 million years ago, although we do not know how. Throughout evolution, many different viruses have inserted genes into our DNA. However, the body has been able to suppress or completely remove the vast majority of these genes. But Arc has been repurposed, and the cells have instead started to use it to regulate some of the processes that control our memory,” says Simon Erlendsson.
“Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins” has been published in Nature Neuroscience. In 2018, the Novo Nordisk Foundation awarded a grant to Simon Erlendsson for the project Synaptic Plasticity by Viral Mimicry.