This Is MS Multiple Sclerosis Community: Knowledge & Support

My thought on the efficacy of antibiotics is that the pathogen is stimulating a heat shock-type/stress response in the cells. When a pathogen invades a cell or tissue, the pathogen tries to set up its optimal conditions: altering the pH, changing the ionic milieu, taking over transcription machinery (polymerases), and translation machinery (ribosomes). The pathogen will replicate or go into a latent phase to replicate at a later date. The cell, on the other hand, responds with a stress response: releasing chaperone proteins to try to refold disrupted proteins, ubiquitinating proteins to mark them for degradation if they are beyond salvage, methylating DNA in the hopes of silencing foreign genes and, if all else fails, going into apoptosis to protect its neighbors. Normally these episodes of invasion and stress response resolve themselves in MSers and non-MSers. However, it is my belief that, in a very few cells, due to some earlier chromosome damage, epigenetic control has been compromised so that the cell overexpresses some of its genes. When the cell attempts a stress response, it overreacts and hampers its normal functioning, which could be myelin formation. So, the antibiotics remove the bacteria and therefore the cells are not stressed into overreacting.
That's pretty vague mumbo-jumbo. So I will give you the details that I have in mind. Of course I needn't remind you that this is only hypothesis on my part.
The polyamines are small, positively charged molecules that have many interactions in cells. They are essential for growth and proliferation. Their size, length, and charge distribution give the potential for many unique interactions, particularly with the negatively charged DNA, RNA, and phospholipids (some of which are in myelin). Their unique characteristics can also make them competitors with histones that package genes, and with specialized proteins like MBP. The main polyamines in cells are: putrescine (+2, about 8 angstroms long, also called a diamine, +NCCCCN+), spermidine (+3, 10-14 angstroms, +NCCCCN+CCCN+), and spermine (+4, 14-20 angstroms, +NCCCN+CCCCN+CCCN+). Normally, prokaryotes (bacteria) express putrescine and spermidine. They do not use spermine. Eukaryotes (mammals and such) use spermidine and spermine, and only transiently have putrescine around. Polyamine levels are tightly controlled because of their potential interactions. They are elevated in many cancers. They are the target of much research since inhibiting them may reduce tumor growth.
Putrescine is used to make spermidine by the enzyme spermidine synthase. Spermidine is used to make spermine by spermine synthase. Some of the polyamine genes are considered to be heat shock genes in that they are induced when a cell is stressed. So bacteria are secreting putrescine and spermidine to control their ionic environment and the cell goes into a stress response. Usually polyamines are bound to something (DNA, RNA, phospholipids) but now from the cell and the bacteria there is an increase in
free polyamines. What if there were overexpression of spermine synthase in a few cells due to chromosome damage? (I can present a very strong case for this but maybe in another post when I have more time to write.) The putrescine and spermidine could be converted to spermine, causing an imbalance in the spermidine/spermine ratio. How important is this? You have probably never heard of the quaking or jimpy mouse strains but they are probably the best models for MS. They both have progressive neurodegeneration from early in life. This has been attributed to an altered spermidine/spermine ratio compared to controls (ie. more spermine, less spermidine). Look at: Russell DH, Meier H. Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice. J Neurobiol 1975; 6:267-274. Spermidine appears to be an important component of myelin. Giorgi PP. Spermidine: a constituent of the myelin sheath? Neurosci Lett 1978; 10:355-340. Recently, a research group in California reported that they were finding myelin in lesions had alterations in the overall charge, more positive than normal. Sorry I don't have that news item handy but I will post it if I can find it. My thought is that spermine may be substituting for spermidine since there is an abundance in spermine relative to spermidine in the cells with chromosome damage. This could also interfere with the normal assembly of myelin and the role of MBP. There are some other consequences of polyamines I will list by giving you some references. Koenig H, Goldstone AD, Lu CY. Blood-brain barrier breakdown in cold-injured brain is linked to a biphase stimulation of ornithine decarboxylase activity and polyamine synthesis: both are coordinately inhibited by verapamil, dexamethasone, and aspirin. J Neurochem 1989; 52:101-109. Scott RH, Sutton KG, Dolphin AC. Interactions of polyamines with neuronal ion channels. Trends Neurosci 1993; 16:1502-1510. Williams K. Modulation and block of ion channels: a new biology of polyamines. Cell Signal 1997; 9:1-13.
Don't go trying to self-medicate based on anything I've written here! Remember it is just hypothesis and could be wrong. It certainly is not easy to test. Isn't it interesting that I didn't mention autoimmunity or genetics? The chromosome damage I am thinking about would not occur at a specific spot in a specific gene everytime and the autoimmune reaction is something that occurs later if at all.
This is only part of a hypothesis I've been developing for a number of years on the so-called autoimmune diseases. A few years ago I published an article called 'Autoimmune diseases are antigen-driven, epigenetic diseases' in Medical Hypotheses. That was a cruder version of the hypothesis. I recently published an article 'Autoimmune disorders result from loss of epigenetic control following chromosome damage' in the online version of Medical Hypotheses. Unfortunately, even though I wrote it and paid to have it published, I can not see it or link you to it because neither I nor my institution have subscriptions. I have asked for permission to post or link to the article but the journal hasn't responded yet. I have a pdf file but copyright restrictions prevent me from just sending it out. No matter. I am writing a longer version and recreating the figures so I can post it on ThisIsMS. I have been writing the longer version but we have been dodging hurricanes, having a house remodeled, and moving all this summer so it has been difficult to finish writing. Once I get the article posted on ThisIsMS or if you can reach it on Medical Hypotheses, I would appreciate any feedback, critiques, X prizes, etc.
Sorry about the length of this post but it is not an easy disease or hypothesis to discuss in brief is it?
Wesley



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Wesley,

I'm afraid I have more questions than comments at this point.

"Selective" chromosome damage? How?

A lot of things can affect ion channels, including endocrine dysfunction. I'm interested in finding out more about polyamines' physiological interactions.

Antigen "driven"? Without triggering T cell response? I'm following you, BUT..........I guess I'm not clear on what you are referring to with that phrase. How can there be antigen "driven" pathogenesis without affecting MHCII? Polyamines bypass MHCII? Thereby again not producing an effect on ion channels? Or are you saying that polyamines help to block ion channels? Do they assist with maintaining sodium density?

What about sulfatides and GABA, not to mention Nogo (referring to myelin, that is)?


I guess I need to read more about this.

Very interesting..........

Deb

Ok....I did a quick speed-read on polyamines.

I have more questions than ever. I can see the direct link of polyamines with cancer cells, since polyamines promote regeneration (hence if they bind to cancerous cells, there would be growth.)

I see where they interact with mitochondria, but I also see where they act as "promoting, modulating or protective agents in mitochondrial-mediated apoptosis" (Interaction of biologically active amines with mitochondria and their role in the mitochondrial-mediated pathway of apoptosis. Toninello A, Salvi M, Mondovi B. Curr Med Chem. 2004 Sep;11(17):2349-74.)

I'm also confused about recent findings regarding spermedine and spermine as published in "Spermine synthesis is required for normal viability, growth and fertility in the mouse. Wang X, Ikeguchi Y, McCloskey DE, Nelson P, Pegg AE. J Biol Chem. 2004 Sep 30 [Epub ahead of print]"

I really look forward to learning more and hearing more about your hypothesis and how it relates directly to myelin and axonal damage in MS.

As I said, I know nothing about polyamines, so I might throw more questions at you than comments! I hope you don't mind, Wesley. I'm a curious one!

(This is getting good...............I love these kinds of discussions, Wesley!)

Ok.....I'm off to read a good book now. Fiction, that is! It's getting late here in Tennessee. LOL (Well, ok, so I'm an early bird.)

Have a great night, all!

Deb

OddDuck,
I will try to answerthe questions I gathered out of your post. We probably need to move this to a new topic though because it is going away from the original topic.
'selective chromosome damage' - I didn't use the word selective. The chromosome damage I envision is chromosome fragmentation, double-stranded breaks in the DNA. There are some sites in chromosomes that are more suspectible to breaks than other sites and these fragile sites can be 4 million bases long. So, if two cells in a person have breaks in the same fragile site, the breaks could be at different points in the fragile site with possibly many genes in between them so that the fragmentation and gene separation in the two cells could be different. So it is not a specific site in a specific 'MS gene'. Another type of damage could be the insertation of viral genes into the host genome. This too could disrupt the normal packaging and expression of host genes. You'll understand better what I am envisioning when I can give the specifics for the hypothesis, but that will be an especially long post.
'polyamine physiological interactions' - I intentionally used the word interactions since polyamines have alot of potential interactions. I did not use functions because not many specific functions of polyamines have been determined. Spermidine can improve translation efficiency by binding transfer RNA and holding the charged amino acid in the best orientation as the tRNA-aa enters the ribosome. Spermidine can also be converted to hypusine in modification of eIF-5A (a translation initiation factor). Spermine can stabilize Z-DNA, but is that an in vivo function? We don't know yet. Z-DNA is thought to be only transient in vivo and I have seen estimates from 0.1-12% of the genome could form Z-DNA. Could be a very interesting function to modulate gene expression rates and to disrupt normal histone/DNA associations. Polyamines can stimulate acetylation of histones. Exactly how is not known but this would loosen the hold of histones on DNA, perhaps opening up genes for more accessibility. Lots of interactions for polyamines but few established critical functions. Polyamines can neutralize some of the DNA's negative charge, reducing the self-repulsion of DNA to prevent it from rupturing the nucleus. So in cancer with continuous DNA synthesis, elevated polyamine levels would be necessary for the cancer cells to continue living. Polyamine synthesis inhibition is a potential means of attacking tumors.
'Antigen-driven' - A cell, for example a skin fibroblast generats an antigen, perhaps from an invading virus or perhaps from some abnormal gene expression or protein modification occurring in that cell. The immune system then reacts tot he antigen. This is opposed to 'immune system driven' in which the immune system goes haywire (or at least a subset of T-cells) and starts attacking perfectly innocent cells. Alot of immunologists have held the idea that autoimmune diseases are immune system driven, whereas I have always felt that they are more likely antigen-driven. I have presented my hypothesis to some of those immunologists. They were polite and all but it is frustrating to try to convince them. I've had to develop a thick skin but it also makes me more determined to keep working on my hypothesis.
We need to study immune reaction events at their earliest because of the potential fogginess of epitope spreading. Epitope spreading is where an initial antigen, say foreign DNA, provokes the immune response, but that DNA is often encountered in association with the host's histones. The immune system then can start reacting to the DNA/histones, and then to the histones by themselves, guilt by association. So, once an autoimmune reaction occurs, it is difficult to see what were the initial precipitators.
'polyamines help to block ion channels' - How polyamines modulate ion channels is still under study but one theory I have heard is that spermine (+4) could enter the calcium channel and bind the negatively charged residues that act as stepping stones for the calcium ions (+2). This would shutdown calcium movement through that channel.
'sulfatides, GABA, Nogo' Can't say I know much about them or myelin composition. I need to learn. I understand it is still being determined. My interests until recently were lupus for developing the hypothesis but I saw the hypothesis could also apply to MS and RA. The same or similar mechanism could be occurring in them but have different consequences based on the cell type. I was on a forum the other day where one person was complaining about hair loss and another was complaining about how tired they got from sun exposure. You would think I was on a lupus forum, but it was actually an MS forum. Lupus is considered a connective tissue disease. Connective tissue is made of collagen. Collagen is rich in proline due to the unique structure of proline and the bending it gives to the peptide backbone, which is needed in the collagen structure. Proline is synthesized from ornithine. But if there is increased synthesis of polyamines, more ornithine is going to polyamine synthesis (ornithine is converted to putrescine by ornithine decarboxylase) and less is available for proline/collagen synthesis. The vulnerability of fibroblasts and chondrocytes then could be their need for proline, whereas in oligodendrocytes it is a need for spermidine in myelin formation. In both, spermidine is necessary for efficient translation and spermine can affect ion channels. Different cell types also differ in their accessibility to T-cells and antibodies so that timing and intensity of an autoimmune reaction could vary as well as the auto-antigens that are released. Isn't it true that lupus patients have CNS problems and MS patients can have photosensitivity? Both can have Sjogren's syndrome. Same mechanism perhaps in MS and lupus, maybe we should consider them to be the same...No, I'm thinking heresy again.
As for the articles you mentioned, polyamines in some cases can inhibit apoptosis and in other cases stimulated apoptosis. More of the confusion that surrounds polyamines. They can (through spermidine/spermine N1-acetyltransferase [SSAT], and polyamine oxidase [PAO]) cause apoptosis by creating peroxides that attack the mitochondrial membrane. They could also protect DNA from nucleases by binding to them and perhaps modulating calcium ion flow, some nucleases being more active with either more or less calcium present (can't remember which off the top of my head).
As for the spermine synthase [SpmS] work, I was aware of that since I work with that group. They did not monitor polyamine excretion, which can be important in stabilizing polyamine levels. Also they did not mention SSAT which can acetylate spermine and convert it back to spermidine. The SSAT gene is actually next to the SpmS gene on the X. Their results were that overexpression of SpmS did not give much change in spermine levels. This was constituitive expression in most cells from embryogenesis on. The cells could balance against this, for example, with increased calcium channels perhaps to help balance excretion of excess spermine. So the cells could develop a tolerance. Also, sometimes overexpression of a protein can lead to its accumulation in clumps so that, even if it is active protein, it does not have extensive access to its substrate. Remember, most polyamines are bound. It is only at certain points in the cell cycle or stress that there are alot of free polyamines. Ornithine decarboxylase [ODC] and S-adenosylmethionine decarboxylase [SAMDC] are the rate limiting steps in polyamine synthesis and they are some of the most tightly regulated enzymes in the cell. When they are active, then there will be free putrescine and decarboxylated SAM [dcSAM] available for further polyamine synthesis. The same authors, however, in an earlier work reported that overexpression of ODC and SAMDC did not cause alterations in polyamine levels. They believe that there are other mechanisms in action in the cell to balance polyamine levels. That certainly seems logical. The scenario I envision for detrimental overexpression of SpmS is in a stress response where there is a rapid increase in free polyamines and the cell can not moderate its polyamine levels quickly enough. Perhaps there needs to be a counterflow of ions into the cell, like calcium ions, as polyamines are transported out. But spermine may be blocking some channels and perhaps the cells have some deficiency in transporting calcium and the interplay of vitamin D with that. Probably something that needs to be developed properly in youth. This is the confusing picture that exists regarding polyamines. They are important and tightly regulated, but then sometimes there seems to be no need for the controls. It points to the large amount of knowledge we are yet to determine about polyamine flows and interactions. Anyway, I think I should start a new topic for any further discussion. But keep the questions coming.
The only thing worse than the apathy of immunologists to new ideas is the apathy of those most affected.
Wesley

Oops, you're exactly correct, Wesley. My apologies. I did go off on subjects outside of this thread, didn't I? We can move them, though, to a new thread.

Hey! Care to take a look at whether and/or how desipramine may apply with your hypothesis? I'm rewriting my original paper (with footnotes this time), trying to integrate all of my compilations that I've continued to find over the past few months into one fairly legible presentation.

As you so aptly noted, there are SO many overlaps between these neurological conditions, that I voiced myself many times that it becomes difficult to tell where one leaves off and another begins!

Wish me luck on my paper! HAH! It's hard to condense all this work down. Plus, as you can see, I like to highlight in different colors!

Deb

Great! Thanks, Arron for moving this to a new thread.

Wesley, a thought: The difficulty I see with ion channels is they have found recently that part (I believe a BIG part) of the reason for permanent disability in MS is because of too much calcium influx. No matter which direction I come from (even regarding chlamydia pneumoniae), what seems to be of great benefit in MS is to control the influx of CA2....inhibit it.

Oh, yea, I did some research on collagen, too, and although I can't exactly tell you how/why, I found it to be something of a dead end in MS.

You've put a lot of things to think and talk about in your last post. And I thought I was "bad"! hehehe........... I'll probably be posting "Oh, yea" comments for days! HAH!

Thanks, though..........it's very interesting stuff!

Deb

As a matter of fact, here's an "oh, yea" comment right now:

Wesley: I know what you mean about trying to discuss theories with the immunologists (especially). So far, though, I've been lucky enough (or perhaps just tolerated) to have the NMSS still interested in at least keeping abreast of my research. To what end, I'm not sure yet.

They can't do anything with it except keep my hypotheses in mind when reviewing new applications for research grants and funds. But, hey.....maybe that in and of itself is something, though, huh? I just thought of that.

Regarding my mention of PTX3, I offhandedly said to the NMSS, "Hey, this might make a good grant application to approve should one come in regarding research into 'PTX3 and MS'." To date, although the connection is there, I see where no researcher is onto it yet. It's pretty new. I keep watching, though. The last I knew from a couple of weeks ago, the NMSS had literally a little over a hundred grant applications they were weeding through.

(Hey...........nobody said I wasn't outspoken. hehehe.......)

Deb

Geez...last post for a bit. LOL

Wesley: Have you looked at my thread regarding PTX3? You know, it might be interesting to you. PTX3 "may" be substantive somehow and perhaps fit in with your antigen driven hypothesis. I'm not sure, though, as I'm just saying this off the top of my head without much thought.

In it, there is mention of transcription factors and their genetic interactions in mDA neurons, and I refer to an article you may find interesting:

"Blood, 15 December 2000, Vol. 96, No. 13, pp. 4300-4306

IMMUNOBIOLOGY

The Long Pentraxin PTX3 Binds to Apoptotic Cells and Regulates Their Clearance by Antigen-Presenting Dendritic Cells"

PTX3 may also be a something of a factor in helping to explain gender differences, also.

As I say, though, these are VERY preliminary compilations, and to date, I don't see where too many researchers have started investigating this yet.

I just thought you might find it to be something you could look into yourself and see how or whether it fits in with your research.

Deb

A problem I see in many theories about autoimmune diseases is that they don't address some of the basic known facts, such as the female predominance. If a particular virus is said to cause MS or lupus or RA, why is it primarily females who get the disease? Males should be just as susceptible but there is never an explanation given as to how virus X selects for females more than males to cause MS, lupus, or RA. We sometimes hear of a discovery of a 'lupus' gene or an 'MS' gene. However, not much if any detail is given as to how the gene causes the disease or why there is a female bias.
The female predominance is suggestive of involvement of estrogen, the X chromosome, and/or X inactivation. Estrogen perhaps has a modulating role in the diseases, but this leaves male suffers as a puzzle if estrogen is always a prime factor. The X chromosome could be the problem since males have an X, but no specific genetic changes in the X have been cited related to autoimmune disorders that I know of. Of course the X is involved in a number of other diseases. Perhaps in the so-called autoimmune diseases epigenetic changes on the X chromosome are involved. One area of epigenetics that is only recently being researched (~last 10 years) in detail is X inactivation.
There have been studies as to the skewing of X inactivation in lupus, ie. is the paternally-derived X more often inactivated or the maternally-derived X? I don't believe there was any agreement on whether there is skewing or not, but the skewing question is based on trying to find a genetic difference the father's and mother's X. Other than that, I have not seen discussions of X inactivation or X epigenetics in relation to autoimmune diseases.
So why not consider so-called autoimmune diseases in relation to cellular stress responses and epigenetic irregularities, particularly X-linked?
I'll give a description of X inactivation and how I think it is involved in my next posts, but I need to do real work now. Maybe I can type more during my lunch.
Wesley

Wesley,

Not to get too far off point, but during my recent research over the last couple of days regarding polyamines (so I can become more familiar and hopefully can speak with you at least SOMEWHAT more intelligently) I came across something that made me chuckle.

As a little background, one of the things I do is drink green tea. So far, I've had every neuro laugh at me about that. My PCP supports it, but the neuros tend to wrinkle their noses at me. (Not that I claim it's some sort of cure-all....not at all. I just say I drink a little, figured it wouldn't hurt...might help. They still wrinkle their nose and chuckle. No problem, I don't mind. I just laugh back at them, too. LOL)

Anyway, I found the following during my cramming sessions on polyamines:

Carcinogenesis. 2004 Sep 16 [Epub ahead of print] Related Articles, Links

Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice1.

Paul B, Hayes CS, Kim A, Athar M, Gilmour SK.

Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096.

Tea polyphenolic constituents induce apoptosis in cancer cells but not in normal cells. To study the mechanism of this selective effect, we used the ODC/Ras double transgenic mouse model that develops spontaneous skin tumors due to overexpression of ornithine decarboxylase (ODC) and a v-Ha-ras transgene. Administration of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the drinking water significantly decreased both tumor number and total tumor burden compared to untreated ODC/Ras mice without decreasing the elevated polyamine levels present in the ODC/Ras mice. EGCG selectively decreased both proliferation and survival of primary cultures of ODC overexpressing transgenic keratinocytes but not keratinocytes from normal littermates nor ras-infected keratinocytes. This decreased survival was due to EGCG-induced apoptosis and not terminal differentiation. Moreover, in skin from EGCG-treated ODC transgenic mice, caspase 3 (active form) was detected only in epidermal cells that possess very high levels of ODC protein. Since most transformed cells and tumor tissue possess higher levels of polyamines compared to normal cells or tissue, our data suggest that the elevated levels of polyamines in tumor cells sensitize them to EGCG-induced apoptosis. These results suggest that EGCG may be an effective chemopreventive agent in individuals with early, preneoplastic stages of cancer having higher levels of polyamines.

PMID: 15375010 [PubMed - as supplied by publisher]
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Not that they'll read this at all, but I just HAD to say "nana nana boo boo"....

(Yea, I'm a nut...... )

Deb

Green tea is being looked at for anti-cancer effects. There are a number of interesting compounds that are being studied to see how they work. It wouldn't surprise me at all if polyamines were one of the areas affected.
Wesley

To continue on the hypothesis...

X inactivation: Normal human female cells have two X chromosomes whereas male cells have only one X. Most of the genes on the X are NOT sex-specific and, therefore, should have equivalent expression in male and female cells. This equilibration, or dosage compensation, is achieved by inactivating one X chromosome in each female cell so that, as a result, there is one active X (Xa) in each female and each male cell. In reality about 70% of the genes on the inactive X (Xi) are inactivated. In those cases where the cell has extra X chromosomes (a female with XXX for example) there is one Xa and all the other Xs are inactivated. Klinefelter's syndrome males (XXY) have an Xa and an Xi.
The Xi (also called the Barr body) has some unique features compared to other chromosomes in the nucleus. The Xi has a perinuclear location, ie. it is usually to one-side of the nucleus next to the nuclear membrane, whereas other chromosomes are spread out in the nucleus during interphase. Interphase is when the cell is not in the dividing stage of the cell cycle. Mitosis is the dividing stage when the cell is splitting into two new daughter cells. The chromosomes are condensed during mitosis, at other times they are spread out.
The Xi has a dense appearance when stained and viewed under a microscope, as if the Xi were tightly packaged compared to other chromosomes. The Xi replicates later than other chromatin. (Chromatin refers to nuclear proteins like histones, transcription factors, receptors, and DNA packaged together. It can mean portions of a chromosome, an entire chromosome, or multiple chromosomes.) The Xi replication is even later than other heterochromatin (epigenetically silenced chromatin). This could make the Xi vulnerable to unrepaired DNA damage since the tight packaging, late replication, and peripheral location can restrict access to DNA damage in order to repair it, and it might elude normal replication checkpoints in the S phase that would otherwise halt the cell's progression into mitosis. A reference you might check is: Brockdorff N, Duthie SM. X chromosome inactivation and the Xist gene. Cell Mol Life Sci 1998; 54: 104-112.
The Xi has some fairly unique components such as localization of ~90% of the cell's macroH2A, a histone-like protein, while at the same time it lacks H2A.bbd (Barr body deficient), a version of histone H2A. Also histone H3 is methylated at lysine 9 (an epigenetic marker). DNA in gene promoters in the Xi is heavily methylated, which appears to aid in keeping the gene silenced. Histone H1 is present in the Xi. H1 is often found in heterchromatin and helps in tighter packaging. Phosphorylation of H1 can alter the tightness of its binding, ie. an epigenetic control mechanism. BRCA1, the breast cancer related tumor suppressor, was recently reported associated with X inactivation. (Ganesan S, et al. Association of BRCA1 with the inactive X chromosome and XIST RNA. Philos Trans R Soc Lond B: Biol Sci 2004; 359: 123-128.) So a variation of this hypothesis may play a role in some breast and ovarian cancers. Remember that the DNA and histone methylation require S-adenosylmethionine (SAM) but polyamine synthesis uses decarboxylated SAM so there could be a competition for SAM between gene silencing and polyamine synthesis.
The most interesting component of the Xi so far is the X-inactivation specific transcript or XIST RNA. XIST RNA is expressed from X chromosomes that have been selected to be inactivated. Copies of XIST RNA accumulate along the X from which it is expressed, coating or painting it so that most of the Xi is covered with copies of XIST RNA. It only accumulates along contiguous chromatin (important point). XIST RNA does not appear to code for any protein and it remains in the nucleus.
more later
Wesley

Ok...so are you then saying that MS MUST be genetically hereditary?

In any event, given the theory you've presented so far, wouldn't this predisposition for neurological/autoimmune disease(s) be evident right at birth? What triggering factor would cause such a DNA disruption post-natally? Geez..........we ARE getting back around to external toxicity!! The similarity to cancer and cancer-causing agents is too close again for comfort!

I ran across a gene therapy hypothesis a few months ago regarding TZDs and the mention therein about the hope of it being applicable in the future for MS. (I'll have to find it. You might find it interesting. I copied it out of a medical journal that we get here at work. I think the main topic of it, though, was diabetes, actually.) Well, that's assuming that you didn't already see it yourself. Boy, full-blown gene therapy is such an unknown avenue, though!! SO tricky!!

Well, I think I'm seeing (at least from my point of view) how and/or why you're sort of coming through the "back door" (my personal analogy) of affecting chromosomes through manipulation of polyamines. Am I close?

By the way, just out of curiosity, have you ever tried to contact David Haffler at Johns Hopkins? Or sent your research to him? He's the top geneticist right now in MS.

Deb

EDIT: Here it is...another "oh, yea" comment: As I mentioned before, desipramine has shown itself to be something of a cross-over from being simply a TCA to being what I term a "mild gene therapy" similar to a TZD. hehehe........... That's one of the things that makes desipramine so "interesting" in its applications. Remember, it also shows efficacy in preventing some type of DNA fragmentation. (I apologize that I can't speak a little more intelligently about it right at the moment. Hence, also, why I'd love to get somebody to REALLY take another CLOSE look at desipramine again....for more reasons than one!) Sorry, had to throw that in there.

I'm not talking about genetics, but epigenetics.
Anyway, to continue-
The X inactivation process begins early in embryogenesis around the time when the rudimentary gut (future digestive tract) is beginning to form. At that point each cell in the body with 2 or more X chromosomes decides in some as yet unknown way which X to keep active, either the paternally-derived or the maternally-derived X. The other X or Xs are inactivated. Then each subsequent daughter, granddaughter, etc. cell will inherit this same inactivation pattern or decision, ie. inactivating the same parentally-derived X. Due to the epigenetic markers (macroH2A, DNA methylation, etc.) the pattern can be passed along.
As a result of each cell in the embryo deciding which X to inactivate, there is a mosaic pattern of X inactivation like a calico cat or checkered pattern such that cells in one site all have the maternally-derived X inactivated and a group of cells near that all have the paternally-derived X inactivated. Kind of reminds you of lesion patterns (hint, important point). Early damage in the X in one cell could be inherited by the daughter cells and on in the one location.
So X inactivation is a normal, epigenetic process to control gene expression but it does have vulnerabilities due to its late replication, peripheral location, and multiple components. There is redundancy built in to keep things inactive but that gives complexity to the process as a consequence. X inactivation is an area currently under intense investigation. It involves a lot of areas that are difficult to explain and many of the insights are less than 10 years old.
This is where pictures would really help. If you think of a depiction of a chromosome as looking like a bow tie with one side longer than the other, turn the bow tie so it stands vertical with the longer side down. The top, shorter side is the short arm or p. The bottom, longer side is the long arm or q. The knot in the center is the centromere and the ends of the bow tie are the telomeres. The banding sections seen in depictions of chromosomes are numbered from the centromere to the telomere. The XIST RNA gene is in the X inactivation center (XIC) at Xq13, about in the middle of the long arm. When the XIST RNA is transcribed (expressed) from the XIC, the copies of XIST RNA coat the Xi in both directions from Xq13 spreading along the Xi to the long arm telomere and along the long arm through the centromere and then along the short arm. The XIST RNA associates with contiguous chromatin, it does not go to other chromosomes.
I’ll continue in a little while.
Wesley

Wesley,

Remember, you're talking to a layperson with only an HS education! HAH!

Ok....I gotta play catchup now. I'll hand it to ya, you've put my mind in overdrive! LOL

And for others who "might" be like me and am struggling, here are some definitions I just now found:

Epigenetics:

The study of how genes produce their effect on the phenotype of the organism

another definition being:

The study of mechanisms involved in the production of phenotypic complexity in morphogenesis.

According to the epigenetic view of differentiation, the cell makes a series of choices (some of which may have no obvious phonotypic expression and are spoken of as determination events) that lead to the eventual differentiated state. Thus, selective gene repression or derepression at an early stage in differentiation will have a wide ranging consequence in restricting the possible fate of the cell.

Phenotype:

The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
The expression of a specific trait, such as stature or blood type, based on genetic and environmental influences.

Morphogenesis

Formation of the structure of an organism or part; differentiation and growth of tissues and organs during development.

Hey, Wesley..............I was close enough in my comments! HAH! ESPECIALLY my comments about "environmental influences". Hey, not bad for intuition, huh?



Ok..... I'll look forward to reading more, but I gotta warn ya, I'm going to need time for the old noggin' to play catch up!

Deb