Sunday, 16 September 2012

Research: nerve repair, is it feasible?

Epub: Kemp et al. Purkinje cell fusion and binucleate heterokaryon formation in multiple sclerosis cerebellum. Brain. 2012 Sep 13.

A major conceptual consideration in both endogenous and therapeutic central nervous system repair is how damaged (or senescent) neurons, given their often enormously complex and extensive network of connections, can possibly be replaced. The recent observation of fusion of circulating bone marrow cells with, in particular, cerebellar Purkinje cells, as well as the subsequent formation of stable heterokaryons (cell with a large number of nuclei), offers a tantalizing potential solution to this difficulty. This study explored Purkinje cell fusion and heterokaryon formation in the human brain and the influence of central nervous system inflammation. The investigators' analysed post-mortem cerebellum tissue from MSers and from appropriate controls. Purkinje cells were analysed for heterokaryon formation using immunohistochemistry techniques and chromosome composition using fluorescence in situ hybridization  or FISH. 

"FISH is a technique used to paint chromosomes so that you can count them or the number of a particular gene in a cell."

FISH - painted chromosome. Are they not beautiful? 
For the first time in humans this study shows a disease-related increase in Purkinje cell fusion and heterokaryon formation. We have shown that heterokaryon formation takes place in control subjects, and that the frequency of this event is considerably increased in MSers, the prototypical inflammatory brain disease, with ∼0.4% of Purkinje cells being binucleate heterokaryons (two nuclei). No mononucleate polyploid Purkinje cell heterokaryons were found. The observation that heterokaryon formation in the cerebellum occurs as part of the central nervous system inflammatory reaction suggests a potential mechanism of neural repair. It also suggests an exciting new avenue for therapeutic intervention, as enhancement or manipulation of fusion events may have a therapeutic role in cellular protection in MS.

Types of neuroaxonal degeneration.

"What is happening here is that cells that are derived from the blood migrate across the blood-brain-barrier, possibly stem cells, and fuse with CNS cells. Heterokaryon is big name to describe an increased number of nuclei and chromosomes. Why do cells need additional chromosomes? It assumed that cells with increased synthetic requirements need more active genes to make enough proteins for the cells survival and functioning; doubling the number of a particular gene from 2 to 4 doubles the potential transcriptional activity of that cell, i.e. the synthesis of messenger RNA that the cell uses to make proteins. This is not surprising when you see how large, and long, nerve cells are. This paper suggests that this is manifestation of repair, however, there is no data that shows this. You have to realise the CNS is very different to other organs in that it is wired in a very complex manner. This is why I am sceptical about fixing or restoring CNS function once a pathway has been damaged; not only do we have to replace lost cells, but we have to coax them into rewiring the pathway that has been lost. Unfortunately, there is another problem called post-synaptic degeneration, which is the loss or death of downstream neurones when upstream neurons die (figure b in the cartoon above). This why we need to focus on the reality of the here and now and try prevent damage in MS before it happens. Fixing damage after the nerve cells and their processes have died is going to be very difficult. task."

10 comments:

  1. What’s the good news then?

    Prof G, I hate to be like some of the more cantankerous MSers that come on to this blog and attempt to undermine you, but when I read a post like this it makes me wonder why on earth I donate money to MS research when I could just as easily, and perhaps more enjoyably, save up and buy an expensive new handbag.

    My MS is a progressive kind and no amount of current medication can remedy that. I’m actually coming to a point where I’m thinking that perhaps I can live with the disabilities I’ve accumulated, but I don’t want to get any worse. The thing is that with every passing moment I am getting worse, but I keep on fighting back extremely hard, hoping my efforts will be rewarded in the long term.

    I have no doubt that restoring lost function will be hard, but in my early years of MS, I would have long periods where I’d be in a wheelchair but then bounce back. Now my disease is just deteriorating with no coming back. I was always hoping that there may be some way to make the nervous system repair itself as it had done in the past.

    On another note, it was only last year that Prof Frrench-constant (and this year in the case of Prof Chandran) stated on Radio 4’s “Fouthought” that CNS repair, they strongly believe, will be a reality within a decade and a half. Who know, maybe their leading us astray, but they court more media attention than anybody else in the field of British MS research and development. Perhaps you will argue that that is an inevitability because they are promising revolution whereas you’re camp is unable to even offer prospect.

    I’m actually coming to a point where I’m thinking that I don’t need a breakthrough any more. I don’t need any promises. I don’t even want to see a neurologist in order to monitor my disease. I don’t need them anymore. They can’t offer me anything and I think I will do better without any of them because I have enough spirit and tenacity to get by on my own. It’s a liberating thought process. No neurologist or MS Society is going to fight as hard for me as I will for myself. I’m not cynical or angry, just enlightened. It doesn’t matter if you can’t ever restore my lost function because I can adapt and overcome, which I sort of am doing. I don’t need any of you for that. (If any of this reads like I’m undermining your profession then I’m sorry for that, but I guess in some ways it’s true.)

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    1. All I am giving is an opinion; I might not be correct. I think you will find that the remyelination strategies that are being pursued by Prof. Charles ffrench-Constant are targeting early lesions, before there is axonal loss. Remyelination strategies won't work if there are no axons left to remyelinate.

      As an MSologist I spend most of my time managing symptoms; DMTs are a tiny fraction of my workload. Most of our patients come to our clinics for help with there symptoms.

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  2. CNS repair

    There is (a) repair of the oligodendrocytes so that they remake myelin...and repair nerve impulse formation and then there is (b) repair of nerves. Regrowing the nerves, then connecting them so the work again and do not cause abnormal sensations.

    The Edinburgh groups mentioned above focus of option (a). Spinal cord injury researchers focus on (b) and this is a harder task than (a). The central nervous system has evolved a system to prevent (b) from occuring in contrast to nerves outside the central nervous system. One has to ask Why? and then How do we best overcome this block?

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    1. I don't know MousedOC. I have to admit though that this post, while perhaps true, is still upsetting to read. I was hoping for real progress in the future. Oh well.

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  3. The progress could come tomorrow or the next day, or next week we dont know what is in the pipeline, likewise we dont know what others around the world are up to. If there are clinical trials things are easier to find because things surface but in the land of science things are submerged until they surface. For example we have been working on some stuff for over eight years that has yet to emerge.

    This is not our line of work at present so we do not have you finger on every pulse. We do not go to those meetings to know what is round the corner. Science is just too broad to be master of every thing. The break throughs often come when one science meets another so it is often not a thing you hear about until it arrives.

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  4. Reply To MouseDoctor
    Sunday, September 16, 2012 11:30:00 PM
    California, "When the MouseDoctor left BC and moved to California, there would be no raise in the average intelligence level in both states." in the land of science all things are science .
    “The Will Rogers phenomenon is obtained when moving an element from one set to another set raises the average values of both sets. It is based on the following quote, attributed (perhaps incorrectly) to Will Rogers: "When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states."It is based on the following quote,” A prophet has no wisdom in his own land ;Okies Science is just too broad to not be master’s of every thing.(Okies Science is God’s wisdom mentored by God ‘s phenomenal, phenomen’s)California, intelligence (artificial intelligence )comes from books and schools that try to teach what men think is phenomenal, of the books of phenomenon’s.” phenomenal wisdom raised the average intelligence level in both states."
    The break throughs often come when one science meets another.
    All science must be based on the same phenomenon’s
    ways .Gods wisdom (science )has no break throughs when man’s wisdom (science) meets true science it is often not a thing you hear about.
    This why we need to focus on the reality of the here and now and prevent MS before it happens;Defining the nature of the DNA-protein interactions that specify the position of the kinetochore and provide a scaffold for kinetochore formation remain key goals
    Propagation of centromeric chromatin requires exit from mitosis":
    A Ti plasmid-encoded enzyme required for degradation of chitin
    A Ti plasmid-encoded enzyme required for degradation of zoospors cysts.major conceptual consideration in both endogenous and therapeutic central nervous system repair is how damaged (or senescent) neurons, given their often enormously complex and extensive network of connections, can possibly be replaced. The recent observation of fusion of circulating bone marrow cells with, in particular, cerebellar Purkinje cells, as well as the subsequent formation of stable heterokaryons (cell with a large number of nuclei), offers a tantalizing potential solution to this difficulty

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    Replies
    1. "When the MouseDoctor left BC and moved to California, there would be no raise in the average intelligence level in both states." in the land of science all things are science .

      Never been to BC must have been some other dumb bloke

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    2. "Offers a tantalizing potential solution to this difficulty"

      Maybe tell us how in Lay English so we can understand

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  5. I have Never been into Lay English, Maybe I can tell you how ,in Lay Az Okies (dumb bloke’s) way of seeing things.If you see something that quits working you find out why.” I am a dumb bloke (dyslexic)I can’t spell or keyboard. I well try to explain in lay Az Okies English cut and paste and with no understanding of grammar .I well go slow so I hope you don’t get lost.”
    All cell’s go into mitosis using one of Two pathways ;if it is worn out (old ),or it is mutated(do to injury )to complete mitosis it must reproduce or be replaced with a reassigned cell that has a copy of it’s DNA. ( a cloned steam cell) All non diploid cell’s are allowed to die. so mitosis repair’s Spinal cord injury like any other injury to cells .
    If a cell is not working it must be traped in mitosis in a womb/ placenta web of chitin ;a zoospore cyst and has counsen-mated (clammed it as it’s zombie ) the mutated cell into a symbiotic care giver relationship ,that must keep it’s host alive, in order to live and reproduce and tap into a blood vein to feed the mutated cell and it’s host in all it’s stages of life ,zoospors responds to injured cell sites as part of the imunein systems responses and takes over, turns off the emergency signals fixes every thing with it’s random web of chitin ( scar tissue ). Then signals your pregnant and that starts the release of hormones that provide for meiosis .......If you don’t believe my tell is true go to the website you well see it to. Look under the hallmarks of mitosis ,zoospors ,scars, chitin and things made by God. Before thinking it must a curse from something ,and give it a name like ms, cancer and, Aids.Do you think the two scinces can meet ?

    ReplyDelete

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