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Thread: Why neurons lose their spark?

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  1. #1
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    Why neurons lose their spark?

    It appears as a consequence of TDP-43 and FUS/TLS proteins getting in a bind outside the nucleus of our motor neurons and not returning to the nucleus, they miss out on manufacturing proteins essential for the continuing function of the motor neuron synapses. True in mice and human cell culture.

    Excess TDP-43 is toxic to the function of our motor neurons.

    The process that causes profilin 1 to clump together is always in the presence of misfolded TDP-43, but there are other processes that cause TDP-43 to misfold that do not affect profilin 1. It would therefore appear that misfolded TDP-43 is a downstream event of the clumping of profilin 1 or the synthesizing of faulty profilin 1 is linked inextricably with TDP-43.

    Profilin 1 is a protein that constructs the motor neuron including the long axon projection that connects to other motor neurons or muscles.

    Also note that the Super Oxide Dismutase(Destroyer) protein also misfolds in SOD1 variant MND. Misfolded proteins are always present at autopsy in MND sufferers.

    Genervon's GM604 therapy reduces the amounts of TDP-43 in our motor neurons. Excellent!


    And for Bob, paracetamol passes BBB and blocks pain receptors in the dorsal horn of the spinal cord in 11 minutes flat!
    Last edited by Graham; 28th October 2014 at 19:22.

  2. #2
    Robert
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    Hi Graham,thanks for that,I thought that had to be the case,with research reports I've read they seem to have a problem with crossing the brain blood barrier.
    In the past if I was to have a sherry it would go straight to my legs making them feel really heavy and ache,this would happen within 10 minutes so I would think another way to cross the BBB.Why I am harping on this is perhaps these readily available products could be used to piggy back whatever through the BBB.

    Regards Bob

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    Hi Bob,

    The sherry will contain ethanol (alcohol) among other compounds. Ethanol will pass BBB and act as a GABA inhibitor in the Upper Motor Neurons causing spastic diplegia, the heavy feeling in your legs. This is an indicator that you have UMN involvement. Ethanol also impacts other brain functions.
    Last edited by Graham; 22nd October 2012 at 12:29.

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    Diseased motor neurons contain between 2-fold and 5-fold amounts of TDP-43 than their healthy counterparts.

    The excess TDP-43 in the cytoplasm of the motor neuron that remains completely unprocessed is particularly toxic to the neuron. Partially processed TDP-43/mRNA is tolerated by the motor neuron. TDP-43 toxic motor neurons are marked for destruction.

    Why excess unprocessed TDP-43?
    Last edited by Graham; 22nd October 2012 at 14:11.

  5. #5
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    The excess unprocessed TDP-43 is a highly charged protein and will unbalance the osmoregulation of the motor neuron.

    The excess TDP-43 within the motor neuron will also cause "molecular crowding". Electrolytic concentration gradients within the motor neuron will be disturbed and will impact cellular processes within the motor neuron.

    The physical presence of the excess TDP-43 means less space is available for other cells within the motor neuron. This will consequently impact cellular processes too.

    One approach for therapy is to rid the motor neuron of excess TDP-43. 58000 compounds have been tested and over 2000 have been identified as being over 30% effective. Testing continues. Thanks Olly. However, merely clearing excess TDP-43 is not going to restore neuron function.
    Last edited by Graham; 27th October 2012 at 02:05.

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    Motor neurons have 'little helpers' that clear tangled TDP-43 and other proteins marked as junk. They are called Proteasomes. The markers of junk protein are called ubiquitin.

    There is a lot of molecular machinery in play and critical gene mutations results in poor quality machinery that cannot function. One such gene mutation makes faulty 'markers of junk', ubiquitin. The proteasome is not able to grapple the marker and feed the junk protein inside its barrel for recycling.

    There are compounds that enhance the performance of the proteasome. One such compound is melittin, found in bee venom. A very interesting experiment carried out on SOD1 mice found that melittin did indeed enhance the function of the proteasome and the mice responded by being more active in life, but lifespan was unaffected.

    We want TDP-43 not to misfold in the first instance, and maintain function in the motor neuron.


    Is it possible to modify gene expression?

    Yes. Phase 1 trials completed during 2012 in Washington USA proved the technique is safe in ALS patients. Called Anti-sense gene therapy, proteins are designed to interfere with motor neuron RNA and block faulty gene expression.
    In June 2014 anti-sense gene therapy work started at Sheffield University, UK.


    Number of genes linked to MND so far discovered: 28

    Faulty genes, associated with familial MND include:

    ___________Gene test___Comment
    ALS2
    ATXN2________________ 19XX Ataxia and eye involvement too. Repeat base genetic flaw.
    Angiogenin_____________ 2012
    C9ORF72____Yes_______ 2011 Causes FTLD / bulbar onset. Repeat base genetic flaw.
    CHMP2B_______________ 2012 Autophagy deficit
    ERRB4_________________ 2013 Recent sporadic genetic mutation
    Fig4___________________ 2013
    FUS
    HNRNPA1______________ 2013 Recent sporadic genetic mutation
    NFH____________________
    Kennedy's disease
    Optineurin
    PFN1__________________ 2013 Recent sporadic genetic mutation
    Profilin 1_______________ 2012
    SETX_________________ 1998 Juvenile onset, 4 known mutations, very slow progressing >30 years
    SOD1_______Yes_______ 1993 Over 100 known mutations of this gene
    TARDBP
    TBK1__________________ 2014
    Ubiquilin 2______________ 2012 Proteasome deficit
    VCP___________________ 2012 Causes FTLD too


    A special mention of repeat sequence bases must be made. It appears the inability of genes to count repeat sequence bbbbases when replicating or maybe viruses home in on these genetic sites when launching their attack.
    Repeat base flaws come in varying lengths. The longer the repeat baaaase, the earlier the onset and more severe the consequences.

    In June 2014 the 'Whole Genome Project' was launched in the UK. 100,000 participants will have their whole genome sequenced of which 1,500 will be drawn from the MND sufferer community.
    Last edited by Graham; 2nd April 2015 at 19:02.

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    What is the mechanism for MND developing?

    Mice with the faulty SOD1 gene develop MND predictably. Mice without the SOD1 gene do not develop MND! It is "faulty" SOD1 gene that "faulty" SOD1 proteins are manufactured(synthesized) from that gives rise to MND.

    Mice with knockout SOD1 gene experience an accelerated motor neuron decline, but not the catastrophy of MND.

    In 2014 a human MND model of the SOD1 variant of the disease revealed faulty SOD1 proteins spreading from one neuron too others in the classic cascade pattern explaining the spread of symptoms that we are all familiar with.
    Last edited by Graham; 13th March 2014 at 19:57.

  8. #8
    Robert
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    Hi Graham, thanks for keeping us up to date with this, it is much appreciated. Hope the fun screws not too tight today, I did say some screws, I did say thumb screws. I am using the Dragon voice activated system, it must be the way I talk, anyway you take care regards Bob

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    Our DNA contains the coding for the biological machine. The coding is very basic and is denoted by only four molecules on the DNA ladder, A' T, C and G. A always pairs with T and C always pairs with G on the DNA ladder. The DNA coils on itself in the first instance and then histones assist the coils to further coil on themselves. The process of coiling further continues until the complete chromosome is formed.

    Technology fitting of the 22nd century demonstrated that individual pieces of the DNA denoted by the letters, A, T, C and G can now be editted with absolute precision using Crispr and SAS9 technology described as 'jaw-dropping' by seasoned professors. This technology supersedes virus techniques of editing DNA.

    The tool for elliminating MND from DNA now exists, but is banned in the UK on ethical grounds, designer babies n all that.

    A BBC article was aired in April 2014 describing precision editing of the yeast genome for uses in making bread.
    Last edited by Graham; 19th October 2014 at 20:10.

  10. #10
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    TREATMENTS IN CLINICAL TRIAL

    Stem Cell Treatments

    BrainStorm - - - - - - - - - Phase 2A. - - - Autologous(self) bone marrow derived stem cells
    FDA Fast Track
    Neuralstem - - - - - - - - - In progress - - - Spinal cord derived neural stem cells
    TCA Cellular Therapy - - In progress - - - Autologous(self) bone marrow derived stem cells


    Other Treatments

    Basiliximab - - - - - - - - Safe
    Dexpramipexole - - - - - FAILED
    GM604 - - - - - - - - - - - - Phase 2A. - - - - - FDA Fast Track, Orphan Drug Status
    KNS-760704 - - - - - - - - Safe
    Lithium - - - - - - - - - - - - FAILED
    NP001 - - - - - - - - - - - - Safe
    SB-509 - - - - - - - - - - - - Safe
    Talampanel - - - - - - - - - Safe
    Thalidomide - - - - - - - - FAILED
    Tirasemtiv - - - - - - - - - - FAILED

    22
    Last edited by Graham; 11th November 2014 at 19:13.

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