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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; 28 October 2014, 21:22.
    Copyright Graham

    #2
    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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      #3
      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; 22 October 2012, 13:29.
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        #4
        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; 22 October 2012, 15:11.
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          #5
          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; 27 October 2012, 03:05.
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            #6
            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___ Year Comment
            ALS2 Yes
            ATXN2______ Yes_______ 1997 Ataxia and eye involvement too. Repeat base genetic flaw.
            Angiogenin__ Yes__________ 2012
            C9ORF72____ Yes_______ 2011 Causes FTLD / bulbar onset. Repeat base genetic flaw.
            CHMP2B____ Yes__________ 2012 Autophagy deficit
            DCTN1 Yes 2018
            ERRB4______ Yes _________ 2013 Recent sporadic genetic mutation
            Fig4_________ Yes _________ 2013
            FUS Yes
            HNRNPA1____ Yes _________ 2013 Recent sporadic genetic mutation
            NFH_________ Yes__________
            Kennedy's disease
            Optineurin Yes
            PFN1_________ Yes _________ 2013 Recent sporadic genetic mutation
            Profilin 1______ Yes ________ 2012
            SETX_________ Yes ________ 1998 Juvenile onset, 4 known mutations, very slow progressing >30 years
            SOD1_______ Yes _______ 1993 Over 100 known mutations of this gene
            TARDBP Yes
            TBK1_________ Yes _________ 2014
            Ubiquilin 2______ Yes ________ 2012 Proteasome deficit
            VCP___________ Yes ________ 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; 13 November 2020, 03:38.
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              #7
              It is a feature of Alzheimer's Disease too that misfolded 'tau' proteins get in a bind in the neuron cell. Indeed, Fronto Temporal Lobar Disease form of dementia is often diagnosed with MND.

              Experimental drug 'Rember' is being touted as the drug to stop Alzheimers by "dissolving" the misfolded proteins in the neuron.

              This therapeutic approach must be of interest to us. Indeed it must be of interest for MND sufferers with FTLD to participate in this trial. Where is MNDA in this?
              Last edited by Graham; 8 November 2012, 14:42.
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                #8
                When our lower motor neurons are stressed, the resident 'police' cells external to the motor neuron, called microglial cells, sense the stress. The microglial cells, otherwise named astrocytes, send out a message 'Call in the cavalry!'.

                These messages exit the spinal cord and locate the 'response team', called monocytes, on patrol in the bloodstream. The messages are specifically coded, 'Motor Neurons in Distress'. For each message received, the monocytes create a battalion of monocytes with the CD14+/CD16- first responders, to rescue the motor neurons. The more distress messages received, more CD14+/CD16- first responders will be created. These are the inflammatory biomarkers for ALS.

                The extent of stress the Lower Motor Neurons are suffering may be measured using the CD14+/CD16-biomarkers.

                The M1 first responders on the scene at the motor neurons hunt for motor neuron cells displaying an 'eat me' tag. Damaged motor neurons are removed.

                It is NP001, chlorite ions, that change the 'Battle Response' to M2, recovery phase prematurely, to save damaged neurons from being eaten.

                An alternative approach being researched is to call off the cavalry by suppressing M1 monocytes. It must be appreciated that both these approaches do not affect the demise of the Lower Motor Neurons, it merely maintains better function of the Lower Motor Neurons during the diseased phase.

                It has been found that the immune response in mice reflects that in humans.
                Last edited by Graham; 12 November 2014, 20:19.
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                  #9
                  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; 13 March 2014, 21:57.
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                    #10
                    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

                    Comment


                      #11
                      Epigenetics reported on Horizon 10 Jul 2013. This branch of genetics has developed just over last two years, enabled by sophisticated computer technology.

                      At the moment the embryo divides in the womb at the genesis of identical twins, each twin has its own copy of the same DNA from which to develop. Identical twins' genetic profiles were analysed in later life and it was found that certain genes were being expressed/turned on in one twin while not in the other. This process appears sporadic.

                      When the gene mutates in adolesence or prior to the act of procreation, the gene mutation will pass on to following generations. However it may be subsequent generations later when the gene mutation expresses itself.

                      In an average lifespan, between 10 and 50 gene mutations may occur.

                      Radio-active element decay radiation, solar radiation and many ingested chemicals cause gene mutation.

                      The human genome is particularly unstable and contrasts starkly with the genome of insects that are extremely stable. For example, the dragonfly's genome has remained largely unchanged for 400,000,000 years.

                      At the human bottleneck of the Lake Toba supervolcano, 72,000 years ago when the human population of earth was less than 10,000, it is highly unlikely MND existed.

                      MND gene mutations are known to be in a single generation, persisted for several generations or run for millenia. The C9orf72 gene mutation is only present in white Europeans. Many of the SOD1 gene mutations are only found in white North Americans while North Indians majorly succumb to slow progression MND variants.
                      Last edited by Graham; 7 July 2014, 00:09.
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                        #12
                        Thanks Graham for the info. I think MND is a gene thing. Interesting that they find sporadic gene changes/switches on , so I guess there isn't any specific cause, just a random change in gene function?

                        Link to BBC news story on gene therapy , it mentions,a neuro degenerative disease and gene therapy towards the end of the article.


                        http://www.bbc.co.uk/news/health-23269778

                        Carol
                        Last edited by Laila; 12 July 2013, 09:26. Reason: Added link to news article

                        Comment


                          #13
                          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; 19 October 2014, 21:10.
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                            #14
                            It is such a pleasure to visit your post Graham, your knowledge is remarkable and i am quite impressed. Thanks for the refreshers.

                            I make sure to not over - indulge in the red wine in future. But 1 beer always make me feel fantastic.

                            I personally find paracetamol to be the best pain killer out there. 500mg usually see me through the day when i badly need it.

                            Best wishes
                            Marieline

                            Comment


                              #15
                              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; 11 November 2014, 20:13.
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