Thursday, July 26, 2007

HERVs and Multiple Sclerosis, part 2

Well, after a short period of distraction, I have just finished reading the new paper from Christopher Power's lab at the University of Alberta. This study follows on from an earlier paper that suggested a causal link between the expression of Syncytin-1, a gene derived from a human endogenous retrovirus (HERV), and multiple sclerosis (MS). The new paper sought to identify the mechanisms by which Syncytin-1 mediates central nervous system damage.

I found it extremely interesting to revisit a subject that I'd read about in detail a few years ago, but ignored ever since. I've clearly managed to neglect a lot of new research; Antony et al. cited a whopping 87 papers, and incorporated new advances in the fields of infectious virology, neurology, biochemistry and immunology into their research.

Much of the work described in the paper focused on the effects of Syncytin-1 on the expression of other cellular proteins; candidate proteins were chosen on the basis of known or predicted involvement in the pathophysiology of MS and other relevant disorders. The Power lab and their Canadian, Japanese and French collaborators approached the problem from various angles. RNA transcript and protein levels were compared in human brain tissue, cultured cells, and transgenic mice that express human Syncytin-1 in specific areas of the brain. After establishing some initial correlations between MS and altered protein expression, the team went on to develop tools to differentiate cause and effect. They were able to manipulate the level of Syncytin-1 protein in cultured cells, either by forced over-expression or by targeted degradation of the corresponding RNA transcript, and show that certain other cellular proteins were specifically misregulated as a result. In this way, the mechanisms of neural damage by Syncytin-1 gradually emerged. The initial event appears to be generation of an inflammatory response, which in turn induces altered expression of proteins involved in cell stress. Ultimately, and as a direct result of Syncytin-1 expression, the myelin coating that protects the nerve fibres becomes damaged - a hallmark of MS.

I've compressed the results of a staggering amount of work into the single paragraph above. This is one of the most comprehensive studies I have ever read – every single finding was confirmed using at least two different methods, sometimes more. Some parts of this paper could easily have stood alone as a full publication. I've seen many a paper based entirely on comparative gene expression analysis in normal versus diseased tissue, or on development of a transgenic mouse model, tools that were both used here as only two parts of a much bigger puzzle. I am hugely impressed. I must admit that when Antony's first paper came out I was somewhat sceptical as I started to read it, having read many other studies showing correlations between HERV expression and diseases such as MS, cancer and schizophrenia. I was always inclined to think that such correlations were more likely to be the result of general transcriptional chaos in some disease states than of pathological HERV sequences. But, in this case at least, it appears that I was wrong; the combined results of these two papers present a very convincing case for the role of Syncytin-1 in the development of MS.

Now that the case has been made so clearly, the field can progress and address some new questions. How does Syncytin-1 expression affect the immune cells that play such an important role in MS? Why does Syncytin-1, a protein usually confined to the placenta, sometimes appear in central nervous system cells and trigger MS? A quick PubMed search brought up some interesting hints. Syncytin-1 expression can be upregulated by viral infection, a condition which is suspected to trigger some cases of MS, and by some signalling molecules associated with MS. In addition, the placental expression of human and rhesus monkey Syncytin-1 changes during pregnancy, suggesting a role for female hormones such as progesterone. As I alluded to in an earlier post, this may explain some aspects of gender-specific MS epidemiology. I hope someone somewhere is working on this problem – not only does it have important consequences for the understanding of this devastating disease, but I also want to know if I managed to be right this time.

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Canada has one of the highest rates of MS in the world. For more information, including how to make a donation, see the MS Society of Canada's website.



8 comments:

  1. Welcome back from Potterland. I'm glad to have you back, coz this is a sweet post.
    Thanks for the great summary.

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  2. Thanks mate! It did take over my life for a few days there, but it had to be done.

    How's the fight against those Texan creationists going?

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  3. Hah, creationists.

    I don't think anything is going to happen any time soon, but I would not be that surprised if McLeroy eventually tries to weasel "ID theory" or the "critical evaluation of evolution" into school curricula.
    My tentative prediction is that the Discovery Institute will contact him about working to get their new "textbook" Explore Evolution included as some sort of supplementary material for high school biology classes.

    Who knows though. I'm trying to get my hands on a review copy of EE, but no one from the DI has returned my email yet.

    : (

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  4. The virions of certain viruses/bacteria are sometimes seen to express pleomorphism, However, this characteristic is in fact not true , since one and the same virion doesn't change shape warranted by a contractile phage viron in metabolic contact with the conjugation “zona” episode leading to oocyst stage and embryo development are endogenously classified pleomorphism of types hence MS/fairly common syndromes, that evolve to the exogenous predisposition to Classification & external resources. But _another group subsequently did_ endogenous retrovirus (HERV)[comparative studies in-vitro]

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  5. Your post is so scientific. I couldn't understand what you describe. Is it about MS origin?

    How this information could be of help for a lay MS-er?

    Anyhow, thank you

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  6. Hi Czes

    Thanks for your comment! I'm sorry the post wasn't helpful to you - most of my readers are fellow scientists, and this was one of the most technical research papers I've summarised on this blog.

    The gist of the paper is that a protein that is produced by a virus (not an infectious virus, but one that inserted into our chromosomes millions of years ago and has evolved along with us ever since) may play a role in the earliest stages of MS. The important part was that by playing around with the amount of the protein in the cell, the authors were able to show that the protein caused cell damage. In the past it was not known whether the protein caused the damage, or the damage caused the extra protein to be made.

    Of course, we still don't know what triggers the cell to make more of the protein in the first place. I imagine that's what this research group is working on right now. Finding that may help to identify factors such as dietary chemicals or infections that trigger MS. So this is very early stage laboratory research that won't benefit patients immediately, but will hopefully make its way into clinical trials eventually.

    I hope that was helpful! Leave me another comment or email me if you'd like more information on the research side of things. I'm not a medical doctor, so lab-based research is the only area I'm qualified to explain!

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  7. Hi !!!. I'have found your blog surfing on internet and I want congratulate you. I am a 50 year old neurologist working in Barcelona, Spain. I made my research thesis on Sjögren's syndrome 15 years ago, when someone told about a relationship between Sj and Multiple Sclerosis (Alexander et al.). We found then positivity of some SS patients against retroviral bands p19 and p24 of HIV-1 and HTLV-I. Now I am trying to go back to this research and I am very interested in looking for retroviral sequences in patients with SS, MS, other autoimmune diseases of brain and, also, chronic fatigue syndrome. I have read the list of papers from you and it's outstanding and I have also got the paper from Power C. et al, and others from Power, that you comment in your blog. I would fully apreciate to get some feedback from you. I don't know if you are aware of a recent paper "T-cell responses to HERVs in HIV-1 infection" in PLOS Pathogens nov 2007.
    Yours sincerely,
    Domingo Escudero, Barcelona Spain
    descuderor@gmail.com

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  8. Hi Domingo, thank you for your comment. Your work sounds very interesting and this is definitely a field that is gaining momentum. However I am not actively engaged in bench research any more (but I do like to read the big papers in the HERV field still), and have not been for a few years now. I would advise you to contact the Power group instead!

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