ERVs and ALS

Posted by ERV on March 8, 2011
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Amyotrophic Lateral Sclerosis, aka Lou Gherigs disease. Pretty much sounds like hell, to me. Your mind is fine, while your body is collapsing around you– slowly but surely paralyzing you, taking away your ability to eat and breathe, while your mind is fine and dandy so you are acutely aware of what is happening to you. If youre lucky, youre dead in 3 years. Not so lucky, it can go on for 6 or more. Terrifying.

What makes it even more terrifying, is that the vast, vast majority of people who develop ALS have no family history of it whatsoever. Wikipedia says 95%.

There is *a* drug for ALS. *A*, that might extend someones life for a few months :-/

No cure. And what makes things even harder, no real definitive test.

Well, scientists have made an odd observation– People with sporadic ALS have a shitload of reverse transcriptase activity in their blood. Like, a shitload. Like HIV-1+ numbers.

OMFG ALS IS CAUSED BY A RETROVIRUS SOMEONE CALL THE WPI WARBLEGARBLE!!!

… Um… Nope. Yeah, scientist can reliably find high RT activity, but cant find virus.

LOL, wut?

Yeah, RT activity all over the place, but no one can find/isolate any actual virus. (Pro-Tip: Its not XMRV) What the hell could cause a phenomenon like that?

I tell you what.

An endogenous retrovirus!

Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis


Endogenous retroviruses are what, everyone?

JUNK DNA!

It is good that they are junk. You want them to be junk. One of the many ways our genome has evolved to ensure that these guys are junk is 1) to epigenetically silence ERVs, and 2) let them accumulate mutations.

Thus the vast, vast majority of ‘ERVs’ in your genome are not full ‘ERVs’, that is LTR-gag-pol-env-LTR. Usually they are just solo LTRs. Sometimes everything is mutated except for a gag, or an env, or… a pol:

Despite clinical associations, past approaches to identify a definite causative viral agent in ALS have been unsuccessful. Here, for the first time, we characterized HERV-K polymerase (pol) mRNA and RT protein in brain tissue from patients with ALS and compared it to non-ALS individuals. We show that there is overexpression of select HERVs in patients with ALS and that HERV from these specific cytogenetic loci may be markers of ALS, as well as other motor neuron diseases.

Quick summary– they looked at the brains of people who had died from ALS, people who died from some other chronic condition, people with Parkinsons, and people who just died from accidents. ALS patients had twice the HERV-K pol mRNA expression as the chronic disease group, 10-fold higher than the Parkinsons and accidental deaths.

There are lots of ‘HERV-K’ loci, though. Is one causing all the trouble, or is this a global effect, an increase in transcription of all HERV-Ks? While lots of patients expressed lots of HERV-Ks, only one HERV-K loci was totally unique in the ALS patients, one on the long arm of Chromosome 7. However, only 6 of the 20 ALS patients showed transcription at that particular site, so no silver-bullet there.

Now, something that Larry Moran always reminds us of, when looking at mRNA levels– Our ability to detect itty-bitty-teeny-weeny changes in mRNA transcription does not necessarily mean that there is any damn difference. You have to establish that those differences in mRNA levels actually translates into differences in protein levels. So, the next thing they did was look for RT proteins via immunofluorescence. Antibody to HERV-K RT is linked to a fluorescent protein, ie, the protein ‘lights up’ if its there, the image is dark if its not there. ALS patients brains light up when they look for HERV-K RT.

Okay, then! Wayward HERV-K expression causes ALS then! HUZZAH!

Not quite.

See, another protein is overexpressed in the brains of people with ALS, TDP-43. Cells that have wayward HERV-K RT expression also have wayward TDP-43 expression. Which means we still dont know if HERV-K expression is 1) the cause of ALS, 2) a harmless side-effect of chromosomal disregulation, aka, just a marker for ALS, or 3) a side-effect of global chromosomal disregulation that perpetuates ALS.

I am leaning against #1, because a clinical trial involving an RT inhibitor in ALS patients did nothing. Probably just a side-effect. In any case, this might lead to putative treatments of ALS like with Hodgkins lymphoma, or at the very least, a diagnostic test looking for HERV-K RT.

Very proud of these authors for not overpumping their data, and making it clear that what they have found “may be markers of ALS”:

These findings identify novel HERV-K and genomic markers of ALS, which may have important implications for defining the pathophysiology of sporadic forms of this disease. However, the mechanisms by which these viruses cause or contribute to pathological changes requires further study.

No hype, just letting the data speak for itself. *nod*

Side-note for long-time ERV readers– This post might sound familiar to you. Very familiar. The difference is, HERV-K RT transcripts in ALS patients are found in neurons, while the HERV-W Env proteins are found in glial cells in MS.

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Comments

  1. #1 Kemanorel
    March 8, 2011

    This is why I love science… that is all I have to say.

  2. #2 Kevin
    March 8, 2011

    If youre lucky, youre dead in 3 years. Not so lucky, it can go on for 6 or more.

    Or, if you’re Stephen Hawking, you live for decades.

    Cool story though. It seems like it would be pretty hard to determine if this is a causative factor. Even if it is, I doubt you’d see anything just over-expressing this gene in mouse brains or something. And if it is a result of aberrant expression, I would expect more of a familial link…

  3. #3 William Wallace
    March 8, 2011

    No hype, just letting the data speak for itself. *nod*

    Contrast with promotion of evolution.

    If youre lucky, youre dead in 3 years. Not so lucky, it can go on for 6 or more.

    You have a strange view of luck.

  4. #4 Mary
    March 8, 2011

    Thanks for the breakdown…I hope this opens the door for anything for ALS…

    I’ve had 6 e-mails already from people trying to link this to ME/CFS, vaccines (autism), and MS…

    The best ALS blog I read was called “Brainhell”

  5. #5 JimNorth
    March 8, 2011

    @William Wallace: you’ve never had a good friend contract ALS, have you?

    On topic – does the HERV-K product end up in the cytoplasm like the TDP-43 or is there an overlap of activities within the nucleus? The little I understand about this issue is from the SOD1 storyline (go free radicals!) where a 1.5 to 2-fold increase in protein levels / activity seems to lead to some dramatic results.

  6. #6 Poodle Stomper
    March 8, 2011

    Kevin,

    I agree although I could imagine a situation where methylation gets messed up (like the epigenetic form of Prader-Willi), allowing expression of the ERV and an immune response against the offending cells. Then it wouldn’t necessarily have to follow in the family. Just an idea. I’m by no means saying this is the case although it does make me wonder if people with ALS have detectably high specific antibodies for the ERV in question. Any ideas ERV (or anyone else)

  7. #7 daedalus2u
    March 8, 2011

    ALS is characterized by high levels of oxidative stress. Oxidative stress is characterized by high levels of homocysteine and a reduction in methylation capacity by the folate and methionine pathways.

    DNA methylation decreases as one ages.

    Methylation of DNA mostly inhibits it. Maybe what is happening is the oxidative stress of ALS is demethylating genomic DNA and allowing endogenous retroviruses (which are normally suppressed by being methylated) to be expressed causing an increase in retrotranscriptase activity.

    TDP-43 is a transcription repressor. It binds to HIV-1 TAR and represses HIV transcription.

    It may be that ALS neurons know that bad shit is going (oxidative stress) on so they are trying to throw everything they can at it, including TDP-43. Maybe the demethylation is the genome trying to find something in all the junk DNA that might do something.

    In desperate circumstances physiology compels you to do desperate things. Maybe even something so desperate as demethylating all your junk DNA.

  8. #8 Rorschach
    March 9, 2011

    Or, if you’re Stephen Hawking, you live for decades.

    it is most unlikely that he has typical ALS, his was very early-onset, and he has survived it for 40+ years. Probably some variant.

    As to HERV, do non-human primates have it ? Do they get ALS ?

  9. #9 ERV
    March 9, 2011

    If its a random, global disregulation of epigenetics–>HERV-K expression, then there should be no familial associations, except in the case of brothers and sisters (common upbringing, common environment, common epigenetic profiles).

    Jim– Im sorry, but I cant help you at all there. Waaaaay beyond my knowledge of whats going on here.

    Poodle– I dont know if anyone has looked for antibodies, or whether they would be there (HERVs are ‘self’). Env can cause damage directly, not sure about RT. Random reverse-transcription, depends on whether integrase is there, eeeeh, seems like cancer would be the ‘damage’, not ALS? Theres got to be something else going on.

    Rorschach– HERV-Ks are the ‘youngest’ ERVs in humans. I dunno if chimps have these, specifically!

  10. #10 daedalus2u
    March 9, 2011

    The issue in ALS is that the motor neurons are dying. Usually, what makes cells die is not enough ATP. If that ATP drop is slow, they do apoptosis. If it is fast, they do necrosis.

    In neurons, ATP is made by mitochondria. Motor neurons happen to be the largest cells in the body, some of them can be a meter long. Virtually all of the metabolic load is out in the cytoplasm (the meter long part), but the protein synthesis is in the cell body next to the nucleus (which is in the spine).

    The metabolic demand of a specific motor neuron can vary by a lot, from a little bit when it is an itty bitty baby motor neuron a hundred microns long, to a gigantic amount when it is a meter long. That is a 4 orders of magnitude increase in metabolic load. That kind of dynamic range requires exquisitely good control over mitochondria number.

    ALS doesn’t happen instantaneously, it takes a few years. When the number of mitochondria is too low, the remaining mitochondria get pushed to a higher potential where fewer mitochondria can make the same ATP, but at a cost of higher superoxide and reduced O2 efficiency (fewer ATP molecules per molecule of O2 reduced to water). Too few mitochondria generate a hypermetabolic state (greater O2 consumption) and a state of oxidative stress (more superoxide production). That superoxide is generated on the inside of the mitochondria and is then dismutated by MnSOD to H2O2. The H2O2 leaks out and is a signaling molecule.

    The familial association in ALS is due to (mostly) mutations on Cu,Zn, SOD. These mutations produce a gain in function, not a loss. ALS is not due to reduced SOD activity. There are about 100 mutations identified, they are spread out all over the molecule, not at the active site. What they do is destabilize the protein so it denatures easier. Especially in the apo (no metal ions) form. One role of apo SOD is to hang around and act as a Cu sponge around things that give off Cu ions when they get “tired” (like mitochondria). Cu is a really bad actor. In the presence of H2O2 it forms hydroxyl radical. Hydroxyl radical destroys anything it touches.

    I suspect that people with ALS have too few mitochondria in their motor neurons and that makes everything worse, more superoxide, more H2O2, more hydroxyl, more apo SOD, more denatured apo SOD. That triggers the unfolded protein response (more oxidative stress). All this oxidative stress lowers the ATP level (via NO signaling through sGC and cGMP) and reduces mitochondria biogenesis (through NO, sGC and cGMP).

    If HERV-Ks are the “youngest” ERVs, then they have had the least amount of random mutations making them replication incompetent and so they would be expected to be expressed first when what ever global genome control system that is keeping them repressed craps out because it “cannae take it any more”.

  11. #11 daedalus2u
    March 9, 2011

    Here is an interesting paper.

    http://www.ncbi.nlm.nih.gov/pubmed/11850021

    I have only seen the abstract, but is the virus causing senescence or is the senescence causing virus expression? My guess would be the latter. I presume in the paper they looked at virus levels over time.

  12. #12 Chris B
    March 9, 2011

    SO the real question to me is, how useful is a screening tool/biomarker approach using this to identify people at risk for ALS? You discussed relative increases over controls, but what about the sensitivity/specificity if it were to be pursued as a biomarker?

  13. #13 daedalus2u
    March 9, 2011

    Correct me if I am mistaken, but these tests require a sample of nervous tissue. I think this research was done postmortem. I don’t think any reputable MD would consider taking a biopsy to test this way. You would have to take samples of nervous tissue that would never grow back. Just taking the biopsy would likely cause the kind of movement difficulties that ALS results in.

  14. #14 William Wallace
    March 10, 2011

    “you’ve never had a good friend contract ALS, have you?”

    No. I have a neghbor a few homes down who seems to have the disease, though. He seems happy–and a nice enough man, and he has not done anything to make me wish he’d die in 3 years instead of 6. Maybe he has something else, because, like I said, he seems happy to be alive, raising his child, with his wife.

  15. #15 Levi
    March 10, 2011

    Thanks for the latest info on this. I was WONDERING what was up with all the RT activity in ALS patients. HERV-K seems like a baddie when the human system can no longer keep it in check:

    1) Breast cancer marker? – http://www.ncbi.nlm.nih.gov/pubmed/18516289?dopt=Abstract

    2)Melanoma progression? – http://www.ncbi.nlm.nih.gov/pubmed/18516289?dopt=Abstract

    3 Testicle destruction? – http://www.ncbi.nlm.nih.gov/pubmed/19459408?dopt=Abstract

    Folks here are talking about methylation factors and poor mitochondria health as possible systemic triggers. Anyone here able to explain to the non-scientist how they might work to unleash this beast?

  16. #16 Richard
    March 10, 2011

    No hype, just letting the data speak for itself. *nod*

    Contrast with promotion of evolution.

    Since no one else has bitten, I will have to here – That is a logical fallacy, you’re not comparing apples with apples. Moreover this blog does not “promote” evolution. Let me explain – evolution is so heavily evidenced and supported by so many branches and disciplines of science that it is beyond reasonable doubt. erv let “the data speak for itself” in this instance because this is new and interesting and the authors of the research paper aren’t jumping to unreasonable conclusions based on the limited research and data – they are waiting for other data and results to support, advance or refute – i.e. the scientific method.

    The fact that evolution is accepted on this blog does not correlate to promotion, that’s just projection your part.

  17. #17 William Wallace67@gmail.com
    March 10, 2011

    Actually, I was thinking of T.H. Huxley (or was that P.T. Barnum?) and other Darwinian cheerleaders who follow, as well as evolutionary fan clubs who aren’t so much inspired by the power of evolutionary theory to predict the future (snicker) as much by the reaction fundamentalists have when children are taught they have descended from beasts.

  18. #18 gillt
    March 11, 2011

    It would be interesting to see if they found similar results in patients with Frontotemporal Lobe Dementia, since it and ALS may be along a spectrum of the same disorder.

  19. #19 Dave
    March 12, 2011

    Fyi: There is an XMRV article in today’s Wall Street Journal. I’ve got the dead tree edition so no linky. Too much “balance” if you ask me, but thought you would be interested.

  20. #20 Jen
    March 15, 2011

    gillt,

    I have a friend who has ALS. He also has a form of that dementia, though most of his memory is the same, it just changed his personality in some ways. His wife and I aren’t sure if it’s a good thing he has the dementia along with the ALS, it all just sucks. He’s 80 years old, and he’s still hanging on, but we don’t know how long he’ll last.