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ERVs and ALS #2 [erv]
Theyre figuring out what the heck is going on in the saga of ERVs and ALS!
2011:
2015:
Human endogenous retrovirus-K contributes to motor neuron disease
1– Of the many ERVs in your genome, the ones they found activated in the brains of people with ALS are HERV-Ks, at two positions: one on chromosome 7 and one on chromosome 10. ERVs degrade a lot over time, but they could find transcripts for all the major retroviral proteins, gag, pol, and env.
Why is this important?
At first, they could only find activity from the chromosome 7 locus, only in some patients. HERV-K activity from chromosome 10 is a new one, for me. There might not be only one HERV-K that can wake up and cause ALS.
Also, they only looked for pol before. It seems the previous work was focused on the enzymes of ERVs, including reverse transcriptase, possibly because RT activity has been detected in ALS patients. Theyve even tried giving people with ALS RT-inhibitors. But in this study, they looked for mRNA from all three major retroviral proteins.
2– The Env protein appears to be the one causing trouble. Again, before scientists were focused on RT. In this study, they looked for the Env protein, and found it in ALS brains. Furthermore, whether they put active HERV-K genomes or only the Env gene into neuronal cells, both were cytotoxic to the cells.
In the absence of any other environmental/physiological/anything, these HERV-K Env proteins are enough, by themselves, to cause neuronal damage.
3– This knowledge could be translated into an Env-expression based small animal model for ALS. They made a transgenic mouse that would express HERV-K Env in neurons. The prefrontal cortex of these animals was fine. It was the upper and lower motor neurons that died. Mice progressively lost motor function.
ALS. “Your mind is fine, while your body is collapsing around you”.
4– What about TAR DNA binding protein 43? In the previous study, TDP-43 was a confusing issue. It was playing a role in this ERV-ALS story, but they couldnt quite figure out where it fit. But now they know HERV-K Env expression alone is enough to cause neuronal damage/ALS-like disease in mice. Whats up with TDP-43?
Point #2? How they could put HERV-K Env in human neurons and see damage? They tried the same experiment, but but TDP-43 in human neurons. Thats it. Nothing else. Guess what happened?
They saw increased expression of HERV-K Env, and cytotoxicity.
They also found *exactly* where TDP-43 was probably binding in the HERV-K DNA to make these unwanted transcripts–>proteins.
This paper has answered a lot of questions about the relationship between ERVs and ALS (some ALS, not enough patients in this paper to definitively say ‘ALL ALS!’), but there is still a lot to do before this translates into any therapies/preventative measures for patients. The main questions for me involve TDP-43, not the ERVs. 1) Why does TDP-43 start snuggling up to ERVs? Whyyyyy? Why would it start doing this?? 2) How the hell can you prevent/stop TDP-43 activating ERVs? Not only do scientists have to figure out how to do it, they then have to figure out how to get this therapy into the CNS. It is *hard* to get any kind of drug in there– its going to suck.
So, good news/bad news with ERVs and ALS– Good news is these folks are really starting to figure out what is going on with this disease. Bad news is, its not RT causing trouble, which explains why RT-inhibitors did nothing for ALS patients. RT-inhibitors would have been a nice, already tested/approved drug. TDP-43-Env relationship will need an entirely new approach.
And, repeat after me, folks:
“The vast majority of ERVs are junk. JUNK DNA. This is a good thing. When junk DNA is accidentally reactivated, BAD THINGS HAPPEN. Not magic unicorn rainbow things. BAD THINGS.”
Source: http://scienceblogs.com/erv/2015/10/09/ervs-and-als-2/
