Tag Archives: siRNA

How does ketamine lift depression?

The incredibly rapid improvement in depression (hours) produced by ketamine is unprecedented and surely is telling us something vitally important about depression.  If only we could figure out what it is.  Clinicians were used to waiting weeks for antidepressants of all sorts to work.  As a neurologist, I’d see it work in a week or so in my MS patients depressed due a relapse.

Two recent papers show just how hard it is going to be [Neuron  vol. 104 pp. 182 – 182, 338 – 352 ’19 ]. First off you have to accept the idea that even though animals (usually mice) can’t tell us how they feel, we still have reasonable animal models of depression (tail suspension test, forced swim test).  We can at least get a handle on anhedonia using the sucrose preference test.

Throw ketamine at an animal and measure the biochemical or the neurophysiologic effect of your choice. There are zillions of them.  Throw just about anything at the brain, and all sorts of things change.  The problem is showing that the change is relevant.  Is the known blockade of NMDA receptors by ketamine how it helps depression.  Give enough and you get out of body experiences and all sorts of craziness, not an antidepressant effect.

Homer1a is a protein found at the synapse, and like all scaffold proteins, it interacts with a bunch of different proteins. It links another type of glutamic acid receptor (mGluR1 and mGluR5) to inositol 1, 4, 5 trisphosphate receptors (IP3Rs) on the endoplasmic reticulum.  It also links mGluR1 and mGluR5 to NMDARs and other ion channels.

So what?

Other work by the authors showed that knockdown of Homer1a (using small interfering RNA – siRNA) in the medial prefrontal cortex (mPFC) abolished the antidepressant effects (in animal models) to ketamine.  Well that’s good, but even better is that knockdown also abolished the antidepressant effects of a tricyclic antidepressant (imipramine).

The present work showed that increasing the expression of Homer1a (the protein comes in various isoforms) in the frontal cortex reduced depression in the various models.

Pretty good — all we have to do is increase Homer1a expression to have a treatment of depression.

Don’t get your hopes up, and this is why depression research is so — well depressing.

Increasing Homer1a expression in another brain region (the hippocampus) has exactly the opposite effects.

Why drug discovery is hard #29 — a very old player doing a very new thing

We all know what RNA does don’t we?  It binds to other RNAs and to DNA.  Sure lots of new forms of RNA have been found: microRNAs, competitive endogenous RNA (ceRNA), long nonCoding (for protein) RNA (lncRNA), piwiRNAs, small interfering RNAs (siRNAs), . .. The list appears endless.  But the basic mechanism of action of RNA in the cell is binding to some other polynucleotide (RNA or DNA) and affecting its function.

Not so fast.  A new paper http://science.sciencemag.org/content/358/6366/1051 describes  lncRNA-ACOD1, a cellular RNA induced by a variety of viruses.  lncRNA-ACOD1 binds to an enzyme enhancing its catalytic efficiency.  Now that’s new.  Certainly RNAs and proteins bind to each other in the ribosome, and in RNAase P, but here the proteins serve to structure the RNA so it can carry out its catalytic function, not the other way around.

The enzyme bound is called GOT2 (Glutamic Oxaloacetic Transaminase 2).  Much interesting cellular biochemistry is discussed in the paper which I’ll skip, except to say that the virus uses the hyped up GOT2 to repurpose the cell’s metabolic machinery for its own evil ends.

lncRNA-ACOD1 has 3 exons and a polyAdenine tail.  There are two transcript variants containing  2,330 and 2,259 nucleotides.  There are only 100 copies/cell.  lncRNA-ACOD1 nucleotides #165 – #390 bind to amino acids #54 – #68 of GOT2.

So what are the other 2000 or so nucleotides of lncRNA-ACOD1 doing?   The phenomenon of RNA binding to protein is quite likely to be more widespread.  Both the GOT2 interacting motif and the interacting sequence of lncRNA-ACOD1 are well conserved across species of hosts and viruses.

Although viruses co-opt lncRNA-ACOD1, it is normally expressed in the heart as is GOT2 with no viral infection at all.  So we have likely stumbled onto an entirely new method of cellular metabolic control, AND a whole new set of players and interactions for drugs to act on (if they aren’t already doing this unknown to us).

This is series member #29 of why drug development is hard, most of which concentrated on the fact that we don’t know all the players.  lncRNA-ACOD1 is different — RNA is a player we’ve known for a very long time  but it appears to be playing a game entirely new to us.

It is also good to see cutting edge research like this coming out of China.  Hopefully it will stand up, but enough questionable stuff has come from them that every Chinese paper is under a cloud.

This is why I love reading the current literature.  You never know what you’re going to find.  It’s like opening presents.