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.
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.