Why drug development is hard #31: retroviruses at the synapse

What if I told you that a very important neuronal synaptic protein Arc (Arg3.1) is acting like like a virus, sending copies of itself (and its messenger RNA) across the synapse?  Would a team of shrinks, who’ve never examined me, tell you that I was crazy and unfit to blog?  Well there is very good evidence that exactly this occurs in one situation and probably many more [ Cell vol. 172 pp. 8 – 10, 262 – 274, 275 – 288 ’18] — http://www.cell.com/cell/fulltext/S0092-8674(17)31509-X.

Arc stands for Activity Regulated Cytoskeleton associated protein.  It’s messenger RNA (mRNA) is transcribed from the gene in response to neuronal activity.  More importantly, the mRNA for  Arc is rapidly distributed to active synapses through the cell body and dendrites, where it is translated into protein. It is locally and rapidly stimulated during the induction of long term depression and plays a critical role in removing a class of glutamic acid receptors (AMPA receptors) from the synapse.  To whet the interest of drug developers, Arc regulates the activity dependent cleavage of the Amyloid Precursor Protein (APP) and beta amyloid production by its interaction with presenilin

Several posts could easily be filled with what Arc does, but that’s not what is so amazing about these papers.  Parts of the Arc protein arose from one of the many transcriptionally dead retroviruses found in our genome.  Our species literally wouldn’t exist without other retroviral gifts.  For instance syncytin1 is a protein expressed a high levels in the placenta.  It is produced from the envelope gene of an endogenous retrovirus (HERV-W) which has undergon inactivating mutations in its other major genes (gag and pol).  Mutant mice in which the gene has been knocked out die in utero due to failure of placenta formation.

Part of the arc gene arose from the Gag gene (Group specific antigen gene) of a retrovirus.  Recall most viruses have proteins coating their genetic material when they’re on the move (e. g. a capsid).  In the case of retroviruses, the genetic material is RNA rather than DNA.  Well the gag elements of the Arc protein form a capsid containing the mRNA for Arc (just like a virus).  In some way or other the capsid containing mRNA gets outside the neuron at the nerve muscle junction and gets into muscle.  The evidence is good that this happens, but in a system somewhat removed from us — the fruitfly (Drosophila).  Fruitfly neuromuscular junctions lacking this mechanism are weaker.

Well that’s pretty far from us.  However one of the papers (275 – 288) showed that the Arc protein and its mRNA was found in extracellular vesicles released from mouse neurons cultured from their cerebral cortex.  Could viral-like particles be crossing the synapses in our brains (which are already pretty chockfull of stuff — see https://luysii.wordpress.com/2017/11/15/the-bouillabaisse-of-the-synaptic-cleft/).  It’s very early times (in fact the Cell issue came out 3 days ago) but people are sure to look.  There are at least 100 Gag derived genes in the human genome (Campillos, M., Doerks, T., Shah, P.K., and Bork, P. (2006). Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589.).

Remarkable.  Remember CRISPR was hiding in plain sight for half a century.  We have a lot to learn.  No wonder drugs have unexpected side effects.

Advertisements
Post a comment or leave a trackback: Trackback URL.

Comments

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s

%d bloggers like this: