connect the dots

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connect the dots

Postby dignan » Wed Mar 21, 2007 8:57 am

I only understand about 20% of the words in the abstract (mostly "and", "in", "has" etc) but it's interesting to me anyway. It seems to tie together a number of different research areas in one study - specifically: pregnancy, endogenous retroviruses, chromosome 7q21-22, TNFalpha, interferon-gamma, interferon-beta and interleukin-6. I don't have a clue what it all means and it could be inconsequential, but so many different aspects of the disease mentioned in one abstract caught my eye, like something shiny.



Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines.

Virology. 2007 Jan 26
Mameli G, Astone V, Khalili K, Serra C, Sawaya BE, Dolei A.
Section of Microbiology, Department of Biomedical Sciences, Center of Excellence for Biotechnology Development and Biodiversity Research, Sassari, Italy; Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900N. 12th Street, 015-96, Philadelphia, PA 19122, USA.

Syncytin-1 has a physiological role during early pregnancy, as mediator of trophoblast fusion into the syncytiotrophoblast layer, hence allowing embryo implantation. In addition, its expression in nerve tissue has been proposed to contribute to the pathogenesis of multiple sclerosis (MS).

Syncytin-1 is the env glycoprotein of the ERVWE1 component of the W family of human endogenous retroviruses (HERV), located on chromosome 7q21-22, in a candidate region for genetic susceptibility to MS. The mechanisms of ERVWE1 regulation in nerve tissue remain to be identified.

Since there are correlations between some cytokines and MS outcome, we examined the regulation of the syncytin-1 promoter by MS-related cytokines in human U-87MG astrocytic cells. Using transient transfection assays, we observed that the MS-detrimental cytokines TNFalpha, interferon-gamma, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-beta is inhibitory. The effects of cytokines are reduced by the deletion of the cellular enhancer domain of the promoter that contains binding sites for several transcription factors.

In particular, we found that TNFalpha had the ability to activate the ERVWE1 promoter through an NF-kappaB-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNFalpha enhances the binding of the p65 subunit of NF-kappaB, to its cognate site within the promoter. The effect of TNFalpha is abolished by siRNA directed against p65.

Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNFalpha-mediated induction of syncytin-1 in multiple sclerosis.

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Postby carolsue » Wed Mar 21, 2007 4:34 pm

dignan,
it is like something "shiny" esp. with all those references to cytokines that I've read about (and not really understood) before! I didn't understand it either, but I think I have an above average ability to read between the lines. What I gleaned is that this study sheds some light on why beta interferon works in MS.

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Postby TwistedHelix » Fri Mar 23, 2007 7:52 am

dignan, I think these scientists must have used an old German Enigma machine to type out this report. I'll have a go at unravelling it, but please end each of the following sentences with a very big "I THINK":

Viruses work by inserting their own DNA into the DNA of the cells they are attacking.

Over the course of evolution, some of that viral DNA has become incorporated into our own genome -- that's what "human endogenous retroviruses", (HERVs), are.

One of these gene sequences is found in a place on a chromosome which has been suspected of causing the genetic susceptibility to MS.

It codes for a glycoprotein, (protein with added sugar!), called Syncitin-1 .

Cytokines are proteins or fragments of proteins which cells use to signal to each other .

Some of these cytokines are known to be bad for MS, while some, like interferon beta, are known to be good.

It seems that all the bad ones, especially TNFalpha , increase production of Syncitin-1, while the good ones reduce it, so it looks as if Syncitin-1 may be quite important in MS.

siRNA, (small interfering RNA), is used in a procedure to stop unwanted gene activity -- it can block TNFalpha, which in turn blocks Syncitin-1.

I think that just about covers it, but I could easily have got it all wrong. There's just one piece of the code I can't crack: something about a German U-boat stationed just off New York......

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Postby dignan » Tue Feb 12, 2008 8:33 pm

Another study showing syncytin-1, a component of a retrovirus, is bad news in the MS disease process.



The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes.

J Immunol. 2007 Jul 15;179(2):1210-24.Click here to read Links
Antony JM, Ellestad KK, Hammond R, Imaizumi K, Mallet F, Warren KG, Power C.
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS).

In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05).

Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05).

Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05).

Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.

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