The viruses in our brains

PNMA2 (ParaNeoplastic antigen MA2) is a protein initially found as the target of the immune response (autoantibodies) producing a nasty dementing neurologic disease (Paraneoplastic encephalitis).  The PNMA2 protein is exclusively expressed in neurons which implies that neurons are using it for something.   This is teleological thinking, usually looked down on, but always needed in molecular biology and cellular physiology.

What PNMA2 does is amazing.  It forms icosahedral viral capsids which are released from cells (in culture) as nonEnveloped capsids.  It isn’t clear if this normally happens in our  brains.    Probably it doesn’t, and when the capsid somehow gets out of the producing cell or neuron immunological hell breaks loose and autoimmune encephalitis is the result.

PNMA2 is derived from one of the long terminal repeat retrotransposons (LTR retrotransposons), viral remnants that make up 8% of the human genome (https://en.wikipedia.org/wiki/LTR_retrotransposon). This explains why it makes particles that look like viruses.  Such particles can contain RNA, so big pharma is interested in them as a way of delivering mRNA drugs.

Totally off topic but yesterday I read a paper about E. Coli DNA gyrase, an amazing enzyme which untangles DNA ( Science vol. 384 pp. 227 – 232 ’24 ).

Here is what it does.   If you’ve got some venetian blinds in your home twist it 20 or so times (keeping the ends fixed, and you have the DNA double helix, with two strands winding around each other.  Now to read or copy a single strand, you must grab both strands where you want this to happen  and pull them apart keeping the ends of the venetian blind fixed.  This immediately increases the coiling elsewhere. Since there are only 10 nucleotides/turn of the double helix, copying a gene for a 100 amino acid protein means you are removing 33 twists from the separated strands (and producing new ones elsewhere).   The cords of the venetian blind quickly become a tangled mess when this happens.  This is where DNA gyrase comes in.  It cuts both strands of the DNA double helix, holding on to the cut ends, and slides an intact double helix of the twisted DNA through the cut.   Sounds fantastic doesn’t it?  Hard to see how evolution could come up with something like this but it did.

The paper contains the following passage toward the end

“A second model based on a sign-inversion reaction wassuggested to describe introduction of (–)SC by this enzyme (28). This model proposed that the enzyme binds to a positive crossover followedby a DNA strand passage through a DNA double-strand break that results in a sign inversion.”

(28) is 28. P. O. Brown, N. R. Cozzarelli,Science206, 1081–1083 (1979).

The paper is 45 years old and has now been shown to be correct.  N. R.  Cozzarelli is my late good friend and Princeton classmate Nick, and it is very nice to see him honored here.

A few words about Nick.  Although Princeton was full of rich kids, they still had the brains to take in someone like Nick whose father was an immigrant shoemaker in Jersey City.  Nick worked his way through Princeton waiting on tables in commons (where all Freshmen ate).  I can still see the time that some rich preppie jerk gave him a hard time about the service.

Nick got his PhD at Harvard and later became a professor at Berkeley where he did his great work.  Nick later edited the Proceedings of the National Academy of Sciences (USA) for 10 years before his very untimely death over 20 years ago from Burkitt’s lymphoma.  R. I. P. Nick.

We wouldn’t exist if retroviruses weren’t moving around in our genome.

Time for some of the excellent molecular biology I’ve put off writing about while I plow through the new Clayden.  I reached the halfway point today (p. 590) Exactly 2 months and 2 weeks after it arrived.  The chemist might need  some brushing up on DNA and messenger RNA before pushing on.  Pretty much all the background needed is found in https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ an d https://luysii.wordpress.com/2010/07/11/molecular-biology-survival-guide-for-chemists-ii-what-dna-is-transcribed-into/.

Everyone has heard of the AIDs virus.  It has so far been impossible to cure because it hides in our DNA doing next to nothing.  Tickle it in a variety of unknown ways, and it’s DNA is transcribed into messenger RNA (mRNA), the virus is assembled and goes on to wreak havoc with our immune system.  How does the AIDs virus get into our DNA in the first place?  Its genome is made of RNA, not DNA.  It has an enzyme (reverse transcriptase) which transcribes its RNA into DNA, and another enzyme (the integrate, which is actually a complex of proteins) which patches the DNA copy (called cDNA) into our genome.  That’s why we can’t get rid of it.  That’s also why it’s called a retrovirus — because of retrograde transcription of its RNA into cDNA).

Well, sorry to say, but at least 10% of our DNA is made of retrovirus remnants.  The vast majority of them have been crippled by mutation so their reverse transcriptases  don’t work any more, or there is something wrong with their integrase, etc. etc.  Some of them do make RNA copies of themselves however, but the copies are mutated enough that infectious virus doesn’t form.  But the RNA copies can be reverse transcribed  into cDNA and reinserted back into our DNA, and in a new site to boot.  This is why they are called retrotransposons.

The whole bunch of retroviruses, retrotransposons, and other repetitive elements of DNA have been called ‘junk’ by eminent authority.  Another epithet for them is the selfish gene — which exists only to reproduce itself.  Humans are said to be machines for reproducing human DNA.

Enter  [ Cell vol. 150 pp. 7 – 9, 29 – 38 ’12 ].  Now it’s time for some very human biology The fetus represents an immunologically different graft to the mother.  Half its antigens are tolerated because they are maternal, the paternal half are not likely to be.  Allogeneic means a transplant from a different member of the same species, so the fetus is regarded as semiallogeneic. 

So why doesn’t our immune system attack the placenta surrounding the fetus, which expresses the paternal proteins?  There’s probably a lot more to it but a class of immune cell called a regulatory T cell (Treg) shuts down the immune response wherever they are found, and the placenta has lots of them.

Different cells express different proteins, and Tregs are no exception. A transcription factor is something that binds to the DNA in front of a gene, turning on transcription of the gene,  ultimately increasing production of the protein the gene codes for. Specificity is obtained by the transcription factor binding to particular sequences of DNA, which are found in only in front of a subset of  genes

The transcription factor which turns on genes necessary to turn an immune cell into a Treg is called Foxp3.  Foxp3 is a protein and to have lots of it around the gene for it must be turned on so its mRNA can be made.  Guess what?  This means that other transcription factors must bind in front the Foxp3 gene.

Here’s Jonathan Swift on the subject

So nat’ralists observe, a flea

Hath smaller fleas that on him prey,

And these have smaller fleas that bite ’em,

And so proceed ad infinitum.”

…

An important protein like Foxp3 is highly controlled.  There are 3 distinct regions in front of the gene were other transcription factors and repressors of transcription bind.  They are called conserved nonCoding sequences (CNSs), an oxymoron, because they are clearly coding for something quite important. The 3 sequences are called CNS1, CNS2 and CNS3.    Technology has progressed to the point where we can remove just about any DNA sequence from the mouse genome we wish (the resultant mice are called knockout mice).  

Anyway if you knockout CNS1 the mice resorb semiallogenic fetuses (where the father and the mother aren’t genetically related), but not allogenic fetuses (where the genomes of the father and the mother are pretty much the same due to inbreeding).  It’s possible to trace Foxp3 far back in evolution.  Only animals with placentas (eutherians) have CNS1 in addition to CNS2 and CNS3. Marsupials, which don’t have placentas, just have CNS2 and CNS3. 

So where do retrotransposons come in?  The structure of CNS1 shows that it is a retrotransposon which moved in front of the Foxp3 gene.  It mutated enough for a new and different set of transcription factors to bind to it and turn on Foxp3 expression in the placenta allowing survival of the fetus.  Some Junk DNA indeed !