Category Archives: Medicine in general

Been busy

I haven’t posted for a while because I’ve been writing a letter to PNAS concerning my idea that chronic fatigue syndrome symptoms are a manifestation of an excess of senescent cells pumping out all sorts of inflammatory proteins into the systemic circulation.  The way to prove or disprove the idea is to measure p15^INK4a in circulating white cells.  The letter is now written and my wife is attempting to put it into English.  For details about the idea please see https://luysii.wordpress.com/2017/09/04/is-the-era-of-precision-medicine-for-chronic-fatigue-syndrome-at-hand/.  Wish me luck that the letter is accepted.

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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.

The bouillabaisse of the synaptic cleft

The synaptic cleft is so small ( under 400 Angstroms — 40 nanoMeters ) that it can’t be seen with the light microscope ( the smallest wavelength of visible light 3,900 Angstroms — 390 nanoMeters).  This led to a bruising battle between Cajal and Golgi a just over a century ago over whether the brain was actually made of cells.  Even though Golgi’s work led to the delineation of single neurons he thought the brain was a continuous network.  They both won the Nobel in 1906.

Semifast forward to the mid 60s when I was in medical school.  We finally had the electron microscope, so we could see synapses. They showed up as a small CLEAR spaces (e.g. electrons passed through it easily leaving it white) between neurons.  Neurotransmitters were being discovered at the same time and the synapse was to be the analogy to vacuum tubes, which could pass electricity in just one direction (yes, the transistor although invented hadn’t been used to make anything resembling a computer — the Intel 4004 wasn’t until the 70s).  Of course now we know that information flows back and forth across the synapse, with endocannabinoids (e. g. natural marihuana) being the major retrograde neurotransmitter.

Since there didn’t seem to be anything in the synaptic cleft, neurotransmitters were thought to freely diffuse across it to being to receptors on the other (postsynaptic) side e.g. a free fly zone.

Fast forward to the present to a marvelous (and grueling to read because of the complexity of the subject not the way it’s written) review of just what is in the synaptic cleft [ Cell vol. 171 pp. 745 – 769 ’17 ] http://www.cell.com/cell/fulltext/S0092-8674(17)31246-1 (It is likely behind a paywall).  There are over 120 references, and rather than being just a catalogue, the single author Thomas Sudhof extensively discusseswhich experimental work is to be believed (not that Sudhof  is saying the work is fraudulent, but that it can’t be used to extrapolate to the living human brain).  The review is a staggering piece of work for one individual.

The stuff in the synaptic cleft is so diverse, and so intimately involved with itself and the membranes on either side what what is needed for comprehension is not a chemist but a sociologist.  Probably most of the molecules to be discussed are present in such small numbers that the law of mass action doesn’t apply, nor do binding constants which rely on large numbers of ligands and receptors. Not only that, but the binding constants haven’t been been determined for many of the players.

Now for some anatomic detail and numbers.  It is remarkably hard to find just how far laterally the synaptic cleft extends.  Molecular Biology of the Cell ed. 5 p. 1149 has a fairly typical picture with a size marker and it looks to be about 2 microns (20,000 Angstroms, 2,000 nanoMeters) — that’s 314,159,265 square Angstroms (3.14 square microns).  So let’s assume each protein takes up a square 50 Angstroms on a side (2,500 square Angstroms).  That’s room for 125,600 proteins on each side assuming extremely dense packing.  However the density of acetyl choline receptors at the neuromuscular junction is 8,700/square micron, a packing also thought to be extremely dense which would give only 26,100 such proteins in a similarly distributed CNS synapse. So the numbers are at least in the right ball park (meaning they’re within an order of magnitude e.g. within a power of 10) of being correct.

What’s the point?

When you see how many different proteins and different varieties of the same protein reside in the cleft, the numbers for  each individual element is likely to be small, meaning that you can’t use statistical mechanics but must use sociology instead.

The review focuses on the neurExins (I capitalize the E  to help me remember that they are prEsynaptic).  Why?  Because they are the best studied of all the players.  What a piece of work they are.  Humans have 3 genes for them. One of the 3 contains 1,477 amino acids, spread over 1,112,187 basepairs (1.1 megaBases) along with 74 exons.  This means that just over 1/10 of a percent of the gene is actually coding for for the amino acids making it up.  I think it takes energy for RNA polymerase II to stitch the ribonucleotides into the 1.1 megabase pre-mRNA, but I couldn’t (quickly) find out how much per ribonucleotide.  It seems quite wasteful of energy, unless there is some other function to the process which we haven’t figured out yet.

Most of the molecule resides in the synaptic cleft.  There are 6 LNS domains with 3 interspersed EGFlike repeats, a cysteine loop domain, a transmembrane region and a cytoplasmic sequence of 55 amino acids. There are 6 sites for alternative splicing, and because there are two promoters for each of the 3 genes, there is a shorter form (beta neurexin) with less extracellular stuff than the long form (alpha-neurexin).  When all is said and done there are over 1,000 possible variants of the 3 genes.

Unlike olfactory neurons which only express one or two of the nearly 1,000 olfactory receptors, neurons express mutiple isoforms of each, increasing the complexity.

The LNS regions of the neurexins are like immunoglobulins and fill at 60 x 60 x 60 Angstrom box.  Since the synaptic cleft is at most 400 Angstroms long, the alpha -neurexins (if extended) reach all the way across.

Here the neurexins bind to the neuroligins which are always postsynaptic — sorry no mnemonic.  They are simpler in structure, but they are the product of 4 genes, and only about 40 isoforms (due to alternative splicing) are possible. Neuroligns 1, 3 and 4 are found at excitatory synapses, neuroligin 2 is found at inhibitory synapses.  The intracleft part of the neuroligins resembles an important enzyme (acetylcholinesterase) but which is catalytically inactive.  This is where the neurexins.

This is complex enough, but Sudhof notes that the neurexins are hubs interacting with multiple classes of post-synaptic molecules, in addition to the neuroligins — dystroglycan, GABA[A] receptors, calsystenins, latrophilins (of which there are 4).   There are at least 50 post-synaptic cell adhesion molecules — “Few are well understood, although many are described.”

The neurexins have 3 major sites where other things bind, and all sites may be occupied at once.  Just to give you a taste of he complexity involved (before I go on to  larger issues).

The second LNS domain (LNS2)is found only in the alpha-neurexins, and binds to neuroexophilin (of which there are 4) and dystroglycan .

The 6th LNS domain (LNS6) binds to neuroligins, LRRTMs, GABA[A] receptors, cerebellins and latrophilins (of which there are 4)_

The juxtamembrane sequence of the neurexins binds to CA10, CA11 and C1ql.

The cerebellins (of which there are 4) bind to all the neurexins (of a particular splice variety) and interestingly to some postsynaptic glutamic acid receptors.  So there is a direct chain across the synapse from neurexin to cerebellin to ion channel (GLuD1, GLuD2).

There is far more to the review. But here is something I didn’t see there.  People have talked about proton wires — sites on proteins that allow protons to jump from one site to another, and move much faster than they would if they had to bump into everything in solution.  Remember that molecules are moving quite rapidly — water is moving at 590 meters a second at room temperature. Since the synaptic cleft is 40 nanoMeters (40 x 10^-9 meters, it should take only 40 * 10^-9 meters/ 590 meters/second   60 trillionths of a second (60 picoSeconds) to cross, assuming the synapse is a free fly zone — but it isn’t as the review exhaustively shows.

It it possible that the various neurotransmitters at the synapse (glutamic acid, gamma amino butyric acid, etc) bind to the various proteins crossing the cleft to get their target in the postsynaptic membrane (e.g. neurotransmitter wires).  I didn’t see any mention of neurotransmitter binding to  the various proteins in the review.  This may actually be an original idea.

I’d like to put more numbers on many of these things, but they are devilishly hard to find.  Both the neuroligins and neurexins are said to have stalks pushing them out from the membrane, but I can’t find how many amino acids they contain.  It can’t find how much energy it takes to copy the 1.1 megabase neurexin gene in to mRNA (or even how much energy it takes to add one ribonucleotide to an existing mRNA chain).

Another point– proteins have a finite lifetime.  How are they replenished?  We know that there is some synaptic protein synthesis — does the cell body send packages of mRNAs to the synapse to be translated there.  There are at least 50 different proteins mentioned in the review, and don’t forget the thousands of possible isoforms, each of which requires a separate mRNA.

Old Chinese saying — the mountains are high and the emperor is far away. Protein synthesis at the synaptic cleft is probably local.  How what gets made and when is an entirely different problem.

A large part of the review concerns mutations in all these proteins associated with neurologic disease (particularly autism).  This whole area has a long and checkered history.  A high degree of cynicism is needed before believing that any of these mutations are causative.  As a neurologist dealing with epilepsy I saw the whole idea of ion channel mutations causing epilepsy crash and burn — here’s a link — https://luysii.wordpress.com/2011/07/17/we’ve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/

Once again, hats off to Dr. Sudhof for what must have been a tremendous amount of work

Antibodies without antibodies

If you knew exactly how an important class of antibodies interacted with its target, could you design a (relatively) small molecule to act the same way.  These people did, and the work has very exciting implications for infectious disease [ Science vol. 358 pp. 450 – 451, 496 – 502 ’17 ].

The influenza virus is a very slippery target.  Its genome is made of RNA, and copying it is quite error prone, so that mutants are formed all the time.  That’s why the vaccines of yesteryear are useless today.   However there are things called broadly neutralizing antibodies which work against many strains of the virus.  It attacks a vulnerable site on the hemagglutinin protein (HA) of the virus.  It is in the stem of the virus, and binding of the antibody here prevents the conformational change required for the virus to escape the endosome, a fact interesting in itself in that it implies that it only works after the virus enters the cell, although the authors do not explicitly state this.

Study of one broadly neutralizing antibody showed that binding to the site was mediated by a single hypervariable loop.  So the authors worked with a cyclic peptide mimicking the loop.  This has several advantages, in particular the fact that the entropic work of forcing a floppy protein chain into the binding conformation is already done before the peptide meets its target.

The final cyclic peptide contained 11 amino acids, of which 5 weren’t natural. It neutralized pandemic H1 and avaian H5 influenza A strains at nanoMolar concentration.

It’s important that crystal structures of the broadly neutralizing antibody binding to HA were available — this requires atomic level resolution.  I’m not sure cryoEM is there yet.

We don’t understand amyloid very well

I must admit I was feeling pretty snarky about our understanding of amyloid and Alzheimer’s after the structure of Abeta42 was published.  In particular the structure explained why the alanine 42–> threonine 42 mutation was protective against Alzheimer’s disease while the alanine 42 –> valine 42 mutation increases the risk.  That’s all explained in the last post — https://luysii.wordpress.com/2017/10/12/abeta42-at-last/ — but a copy will appear at the end.

In that post I breathlessly hoped for the structure of aBeta40 which is known to be less toxic to neurons.  Well it’s here and it shows how little we understand about what does and what doesn’t form amyloid.  The structure appears in a paper about the amyloid formed by another protein (FUS) to be described later — Cell 171, 615–627, October 19, 2017 — figure 7 p. 624.

Now all Abeta40 lacks are the last 2 amino acids of Abeta42 — isoleucine at 41 and alanine at 42.  So solve the Schrodinger equation for it, and stack it up so it forms amyloid, or use your favorite molecular dynamics or other modeling tool.  Take a guess what it looks like.

Abeta42 is a dimer, a beta40 is a trimer, even though the first 40 amino acids of both are identical.

It gets worse. FUS (FUsed in Sarcoma) is a 526 amino acid protein which binds to RNA and is mostly found in the nucleus.  Neurologists are interested in it because over 50 mutations in have been found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).   FUS contains a low complexity domain (LCD) of 214 amino acids, 80% of which are one of 4 amino acids (glycine, serine, glutamine and tyrosine).  At high protein concentrations this domain of FUS forms long unbundled fibrils with the characteristic crossBeta structure of amyloid.  Only 57/214 of the LCD amino acids are part of the structured core of the amyloid — the rest are disordered.

Even worse the amino acids forming the amyloid core (#39 -#95) are NOT predicted by a variety of computational methods predicting amyloid formation (Agrescan, FISH, FOLDamyloid, Metamyl, PASTA 2.0).  The percentages of gly, ser, gln and tyr in the core forming region are pretty much the same as in the whole protein.  The core forming region has no repeats longer than 4 amino acids.

The same figure 7 has the structure of the amyloid formed by alpha-synuclein, which accumulates in the Lewy bodies of Parkinson’s disease.  It just has one peptide per layer of amyloid.

When you really understand something you can predict things, not just describe them as they are revealed.

 

Abeta42 at last

It’s easy to see why cryoEM got the latest chemistry Nobel.  It is telling us so much.  Particularly fascinating to me as a retired neurologist is the structure of the Abeta42 fibril reported in last Friday’s Science (vol. 358 pp. 116 – 119 ’17).

Caveats first.  The materials were prepared using an aqueous solution at low pH containing an organic cosolvent — so how physiologic could the structure actually be?  It probably is physiologic as the neurotoxicity of the fibrils to neurons in culture was the same as fibrils grown at neutral pH.  This still isn’t the same as fibrils grown in the messy concentrated chemical soup known as the cytoplasm.  Tending to confirm their findings is the fact that NMR and Xray diffraction on the crystals produced the same result.

The fibrils were unbranched and microns long (implying at least 2,000 layers of the beta sheets to be described).  The beta sheets stack in parallel and in register giving the classic crossBeta sheet structure.  They were made of two protofilaments winding around each other.  Each protofilament contains all 42 amino acids of Abeta42 and all of them form a completely flat beta sheet structure.

Feast your eyes on figure 2 p. 117.  In addition to showing the two beta sheets of the two protofilaments, it shows how they bind to each other.  Aspartic acid #1 of one sheet binds to lysine #28 of the other.  Otherwise the interface is quite hydrophobic.  Alanine2 of one sheet binds to alanine42 of the other, valine39 of one sheet binds to valine 39 of the other.  Most importantly isoLeucine 41 of one sheet binds to glycine38 of the other.

This is important since the difference between the less toxic Abeta40 and the toxic Abeta 42 are two hydrophobic amino acids Isoleucine 41 and Alanine 42.  This makes for a tighter, longer, more hydrophobic interface between the protofilaments stabilizing them.

That’s just a guess.  I can’t wait for work on Abeta40 to be reported at this resolution.

A few other points.  The beta sheet of each protomer is quite planar, but the planes of the two protomers are tilted by 10 degrees accounting for the helicity of the fibril. The fibril is a rhombus whose longest edge is about 70 Angstroms.

Even better the structure explains a mutation which is protective against Alzheimer’s.  This remains the strongest evidence (to me at least) that Abeta peptides are significantly involved in Alzheimer’s disease, therapeutic failures based on this idea notwithstanding.  The mutation is a change of alanine2 to threonine which can’t possibly snuggle up hydrophobically to isoleucine nearly as well as alanine did. This should significantly weaken the link between the two protofilaments and make fibril formation more difficult.

The Abeta structure of the paper also explains another mutation. This one increases the risk of Alzheimer’s disease (like many others which have been discovered).  It involves the same amino acid (alanine2) but this time it is changed to the morehydrophobic valine, probably resulting in a stronger hydrophobic interaction with isoLeucine41 (assuming that valine’s greater bulk doesn’t get in the way sterically).

Wonderful stuff to think and speculate about, now that we actually have some solid data to chew on.

Abeta raises its head again

Billions have been spent (and lost) by big Pharma on attempts to decrease Abeta peptide in the brain as a therapy for Alzheimer’s. Yet the theory that Abeta has something to do with Alzheimer’s won’t die because it is so compelling.

Here’s another example [Neuron vol. 96 pp. 355 – 372 ’17 ] Neurons in hippocampal slices stop forming new synapses when exposed to Abeta.  We think that synapse formation and elimination is going on all the time in our brains — it certainly is in mice.  For details see an excellent review [ Neuron vol. 96 pp. 43 – 55 ’17 ].  This is thought to be important in learning, something lost in Alzheimer’s as well as old memories. Two Alzheimer mouse models have shown defects in new synaptic spine formation.

Even better the authors found what Abeta is binding to — a well known brain protein — Nogo receptor 1 (Ngr1).  When it was knocked down in the slice (by bolistic short hairpin RNA infererence — shRNAi), spines started reforming.

So the work may explain some of the problems in Alzheimer’s disease but it says nothing about the neuronal loss which is also found.

Also, there is something fishy about the results.  The Abeta preparation used in the experiment was mostly oligomers of about 100 monomers (with a molecular mass of 500 kiloDaltons).  Monomers had no effect.  It is much easier to conceptualize a monomer binding to a receptor than an oligomer.  However, oligomer binding would tend to cluster receptors, something important in immune responses.

The strongest evidence for Abeta in my opinion is the fact that certain mutations PROTECT against Alzheimer’s — and given the structure just worked out we have a plausible explanation of just how this works — for details see — https://luysii.wordpress.com/2017/10/12/abeta42-at-last/

 

Does she or doesn’t she? Only her geneticist knows for sure

Back in the day there was a famous ad for Claroil — Does she or doesn’t she? Only her hairdresser knows for sure.  Now it’s the geneticist who can sequence genes for Two Pore Channels in pigment forming cells (melanocytes) who really knows.

Except for redheads, skin and hair color is determined by how much eumelanin you have.  All human melanins are  polymers of oxidation products of tyrosine (DOPA, DOPAquinone) and indole 5,6 quinone, so its chemical structure isn’t certain.  It is made inside a specialized organelle of the melanocyte called (logically enough) the melanosome.

There is all sorts of interesting chemistry and physiology involved.  In particular a melanosome protein called Pmel17 adopts an amyloid-like structure (so not all amyloid is bad !) for the construction of melanin.  The crucial enzyme oxidizing tyrosine is tyrosinase, and its activity strongly depends on pH, being most active at pH 7 (neutral pH).

In the melanosome membrane is found TPC2, which helps control ion flow in and out of the melanosome.  Two mutations Methionine #484 –> Leucine (or M484L) and Glycine #734 –> Glutamic acid (G734E) are associated with a shift from brown to blond.  You have blond hair if your melanosomes make less melanin.  Both mutations result in an increase in TPC2 activity resulting in lower pH, lower tyrosinase activity and less melanin in the melanosome — voila — a blond.

So it doesn’t take a big (one amino acid in over 734) change in the huge TCP2 protein for the shift to occur.

Who knew Marshall McLuhan was a molecular biologist

Marshall McLuhan famously said “the medium is the message”. Who knew he was talking about molecular biology?  But he was, if you think of the process of transcription of DNA into various forms of RNA as the medium and the products of transcription as the message.  That’s exactly what this paper [ Cell vol. 171 pp. 103 – 119 ’17 ] says.

T cells are a type of immune cell formed in the thymus.  One of the important transcription factors which turns on expression of the genes which make a T cell a Tell is called Bcl11b.  Early in T cell development it is sequestered away near the nuclear membrane in highly compacted DNA. Remember that you must compress your 1 meter of DNA down by 100,000fold to have it fit in the nucleus which is 1/100,000th of a meter (10 microns).

What turns it on?  Transcription of nonCoding (for protein) RNA calledThymoD.  From my reading of the paper, ThymoD doesn’t do anything, but just the act of opening up compacted DNA near the nuclear membrane produced by transcribing ThymoD is enough to cause this part of the genome to move into the center of the nucleus where the gene for Bcl11b can be transcribed into RNA.

There’s a lot more to the paper,  but that’s the message if you will.  It’s the act of transcription rather than what is being transcribed which is important.

The paper doesn’t talk about the structure of ThymoD — how long it is, whether it binds to anything in the nucleus — etc. etc.  Perhaps I’ve missed it.  I’ve written the lead author. Hopefully I won’t be too embarrassed by what he responds.

Here’s more about McLuhan — https://en.wikipedia.org/wiki/Marshall_McLuhan

If some of the terms used here are unfamiliar — look at the following post and follow the links as far as you need to.  https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/

 

How fast is your biological clock ticking — latest results

Our family breeds like sequoias.  Medicine has improved, but biology hasn’t changed, and problems with fertility and miscarriages have emerged in the generation behind me.   A cousin had a child at 46 who is now in grad school.  My brother had a child at 48, also doing OK. One son, who is north of 50 has an infant and a 3 year old.  That’s why the following paper from Iceland is so relevant.  I’ve posted on this subject before, but the new paper has 10 times the data of the old [ Nature vol. 549 pp. 519 – 522 ’17 ].

The paper is from Iceland, and whether the data can be extrapolated to other populations isn’t clear — but the biology in question is so basic that I think it can. Some 1,548 mother father child trios had their entire genomes (to 35 fold coverage).  In addition, 225 of the children had reproduced, providing a few 2 generation families.  If any position in the 3,200,000,000 bases of the genome differs from that of the mother and the father, than a mutation has taken place.  It isn’t clear how old the children were when sequenced, so possibly some of the mutations arose since birth.

Some 108,778 de novo mutations were found in over 1548 + 225 (at least) individuals — so each individual carried an average of 61 de novo mutations.  When the number of mutations were plotted against the ages of both parents, it was found that each year a father waited to reproduce added 1.51 mutations.  Previous work (with much less data) stated that the age of the mother didn’t matter.  No so, although the mutational burden of an additional year before reproduction in a woman increased the mutations 4 times less (.37 extra mutations/year of maternal life).

The previous paper reported on was somewhat suspect, because the 78 parent child trios had a child with autism.  Not so in this population study.

The numbers were large enough, that the type of mutation could be studied.  Mothers and fathers had different types of mutations in different frequencies.   They found one 20 megaBase region on chromosome #8 with a mutation rate of cytosine to guanosine (C to G) 50 times higher than the rest of the genome.

People use ‘molecular clocks’ to time evolution of species, based on the assumption that the mutation rate is constant.  But it isn’t with age, and a shift in the average age for reproduction could seriously screw up the molecular clock predictions.

An average of 61 de novo mutations per individual sounds pretty horrible, but it isn’t when you consider that 3,200,000,000 – 61 positions were copied faithfully (an error rate of 1 in 50 million).

 

The worst name for a drug I’ve ever heard of

It is simply impossible for me to think of a worse name for a drug which might help people with Down syndrome than ALGERNON.   The authors can be excused as they’re all from Japan, but the editor of the paper Fred Gage should have known about ‘Flowers for Algernon’– https://en.wikipedia.org/wiki/Flowers_for_Algernon.  Briefly, it’s a story about a drug which tripled the intelligence of Algernon a laboratory mouse which was then given to a retarded individual (Charlie Gordon) whose intelligence similarly tripled, only to decline like Algernon’s.  It was originally a short story, then a book, then a play etc. etc.

The drug is potentially quite exciting — ALGERNON is an acronym forALtered GenERatioN Of Neurons).  It increases the number of neurons form by mice with a model of trisomy 21.  The brain is bigger, and the animals do better on tests.  It is thought to work by inhibiting an enzyme (DYRK1A) which adds phosphate to serine, threonine and tyrosine, making it a dual specificity kinase.  It phosphorylates a variety of proteins known to have significant effects on brain development (tau, cyclin D1, caspase9, Notch, gli1, etc). The net effect of DYRK1A inhibition is to increase neural stem cell proliferation during fetal life.

Chemists will be interested in just how simple the structure of ALGERNON is — it’s an all aromatic compound made of a pyridine linked to a fused 6:5 ring system in which the 5 membered ring contains 2 nitrogens.  That’s it.  No alcohols, methyls, ethyls, ..  amines, amides, ethers etc., etc.

The authors blue-sky a bit at the end.  They note that mice show neural proliferation during adult life (we do as well, but to a much lesser extent).  It might be useful to improve function in living Down syndrome individuals, and just about any other neurological problem in which neural proliferation would be beneficial.  It might also be offered to women carrying a Down fetus who object to abortion on moral grounds.  Exciting stuff, but for god’s sake change the name.