The brain is a complicated organ. Let’s start there. It’s complicated at every level that you care to examine, and if you get down to the genomic sequences of individual neurons, it’s worse than ever. The sheer variety of neurons and other cell types is quite extreme, and a lot of work over the years has gone into trying to figure out how this huge range of morphology and function is generated. As became clear not too many years ago, on a cellular level the brain is a mosaic tissue: the different cells in it can have somewhat different DNA sequences, distinct but (apparently) rather random. This arises (as far as we know) during development, and leads to single-nucleotide variations, copy number variations in individual genes, and other changes. And like so many odd things that you come across in cell and developmental biology, the odds are that after all these hundreds of millions of years it’s something with utility rather than just this stuff that happens out there in a void – the “Chesterton’s Gate” analogy is very strong in evolutionary biology.
One of the genes that shows a big range of copy number variation is APP, which codes for the (in)famous amyloid precursor protein. That’s a 751-amino acid beast, and the beta- and gamma-secretase enzymes carve out the far shorter beta-amyloid protein from the middle of it. Now, if you ask me why they do that, da bin Ich überfragt, as they say in German, “there I am overasked”, because that’s a major mystery. There’s a (controversial) theory that the beta-amyloid protein itself might be a defense mechanism against infectious disease in neuronal tissue, but it’s safe to say that a great deal of work on APP and amyloid have so far failed to resolve a lot of the “how come” questions.
Now it turns out that the APP gene shows the effects of genetic recombination as well. And how. This paper reports that there are thousands of cDNAs present in human neurons (“gencDNAs”) with variations of APP – all sorts of single-nucleotide variations and intra-exonic junctions, just a real mish-mosh. And these are actually inserted (via reverse transcription) into the genomes of post-mitotic neurons and can be transcribed and translated into new protein species. And they find what they describe as a “marked shift” in both the number and composition of these genomic cDNA species in the tissue of patients who were diagnosed with Alzheimer’s disease, including the sequences of several APP variants that had already been described as causal in the familial forms of the disease.
Those are mutations in APP, ones that make it easier to cleave the protein to give you beta-amyloid, that are associated with greater risk of early onset Alzheimer’s (or at least something that’s close enough to make little difference). There are various family lineages in Sweden, the Netherlands, Colombia, and other countries that have been discovered with such risk-factor mutations, a scary thought for several reasons. This, coupled with the obvious deposits of beta-amyloid itself in all Alzheimer’s-affected brains (the very hallmark of the disease) are why so much time, effort, and money has been spent on the amyloid hypothesis for the disease. I’ve said a lot of disparaging things about it here over the years, but it’s a very compelling story.
And what this means is that any new theory of Alzheimer’s is going to have to encompass the amyloid one. It’s the same sort of thing as when Einstein’s relativity came along. He didn’t invalidate Newtonian physics – he subsumed it into a larger framework. Newtonian mechanics works perfectly well as long as you’re not (say) approaching the speed of light or under the effects of a strong gravitational field – under more “normal” conditions you have to take fanatically precise measurements to see that there’s anything off at all. And so with Alzheimer’s: any true theory of what the disease is and how it develops is going to have to explain all the amyloid connections, because they’re real – but it will also explain why all the efforts to target amyloid (through secretase inhibitors, antibodies, etc.) have not worked. Speed the day of such a theory’s arrival.
This new work might well be part of such an explanation. If the population of human neurons varies so much in its APP profile, developing a single drug to affect a single target might well be. . .well, inappropriate at best, futile at worst. These results could complicate human neuroscience immensely, which if I’m going to be honest is not what I would have asked for. But like any scientist, what I really ask for is truth, for the real details of what’s really happening, with the full knowledge that I might not like it when I get it. The implications, though, go far beyond Alzheimer’s disease:
Additional genes may be transcriptionally modified and genomically retro-inserted in response to selective activities in neuronal populations. Such a mechanism might enable preferential gene re-expression that bypasses splicing or further RNA modification. More broadly, gencDNAs could provide neurons with an activity-dependent mechanism for recording and retaining information over long periods of time, perhaps placing multiple forms of a gene under transcriptional control distinct from a wild-type locus, which could be produced through diverse genomic integration sites that remain to be determined. Such a process could have relevance to known neuronal functions that depend on transcriptional activity including Hebbian plasticity, synaptic wiring, learning and memory, and cognition. Thus, gencDNA production may represent both a ‘recording’ and a ‘playback’ mechanism for expressing a symphony of variants beyond wild-type gene forms. It would be surprising if APP were the only gene to undergo this form of recombination. . .
Oh yes, it would be. This is both exhilarating and terrifying. An entirely new feedback and regulatory universe could be opening up on us here if this pans out, with neurons modifying their own genomic sequences (and the rate and degree of that modification) in response to environmental stimuli. I would add that there may be no reason to suppose that such processes are confined to neurons (indeed, it’s already known that “standard” genetic recombination is how you get the huge variety of antibodies). The advent of numerous modern sequencing technologies on both DNA and RNA species, along with single-cell techniques for their use, has already been telling us (for example) that tumors are far more difficult and complex environments than we’d imagined. But what if our normal tissues are just as variable – indeed, with variability in the variations themselves? Hold on, hold on tight.