ALS News Today Forums Forums ALS Progress Research Topics Enhanced insulin signalling ameliorates C9orf72 ALS in a fly model

  • Enhanced insulin signalling ameliorates C9orf72 ALS in a fly model

    Posted by Jean-Pierre Le Rouzic on March 31, 2021 at 4:20 pm

    Repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, scientists show that insulin/IGF signalling is reduced in fly models of C9orf72 repeat expansion using RNA sequencing of adult brain.

    They further demonstrate that activation of insulin/IGF signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/IGF signalling pathway are genetically activated in the flies, suggesting a mechanism of rescue.

    Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, their data suggest that modulation of insulin/IGF signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

    Jean-Pierre Le Rouzic replied 2 years, 8 months ago 2 Members · 3 Replies
  • 3 Replies
  • Trevor Bower

    April 6, 2021 at 3:46 pm

    Is there a definite correlation between insulin signaling and expressions of ALS? What if the ALS is not correlated with genetics? Is this possible?

  • Jean-Pierre Le Rouzic

    April 7, 2021 at 3:37 am

    > What if the ALS is not correlated with genetics? Is this possible?
    There are roughly two main cases:

    1. Most cases (~90%):
    Most ALS cases are proteopathies (look at Wikipedia): more than 95% are TDP-43 proteopathies and some SOD1 proteopathies exist also.
    A proteopathy is not a genetic disease, it is a disease where misfolded proteins are located in aggregates in the cytoplasm, instead in the nucleus of neurons. The way a protein folds changes its biologic function.
    Most neurogenerative diseases are proteopathies, Alzheimer with beta amyloids and Tau proteins, Parkinson with α-Synucleine.
    That said, a protein are encoded by genes. A gene can encode several proteins. Proteins are the building and signaling materials used in a cell.

    2. Familial cases (~10%)
    People with a mutated FUS, C9orf72, SOD1 or some other genes in a set of ~125 genes have more odds to get ALS when they are aged or submitted to an intense stress.

    That said, the common sense tells that ALS could not be entirely a genetic disease, as contrary to real genetic diseases like spinal muscular atrophy or Duchenne muscular dystrophy, patients do not suffer from ALS until they get old. “Purely” genetic diseases affect people as soon as they are born.

    To complicate the case, ALS is also certainly a metabolism disease, pALS have to have a BMI to be around 27 to maximize their odds to slow the disease, and half of pALS have an insulin insensibility (as if it was a diabetes). I guess that all that is linked, a slightly defective gene, an aging cell with inclusion bodies (to give an image it is as if the cell was a house where trash bags would accumulate over decades) make the body functioning in an altered manner.

    I guess that some scientists or doctors do not expect us to understand complex statements, so they simplify their speech.



  • Jörg Dimmeler

    September 13, 2021 at 2:59 pm

    Und was könnte das für mich heißen?? ich habe C9 ORF72

    "And what could that mean for me? I have C9 ORF72"


  • Jean-Pierre Le Rouzic

    September 14, 2021 at 1:41 am

    > And what could that mean for me? I have C9 ORF72


    Some caveats:
    Nobody knows how to heal from ALS, the article above is a research article, basically it hints that something is wrong in insulin management in a fly model of ALS.
    Flies are insects, they do not even have a spine like vertebrates, scientists use them as they are convenient and low cost. Basically scientists who use flies are like people looking for they lost keys under a street light, because there is light only under this lamp post.

    Yet this article is yet another one that indicates that insulin resistance in some patient is a consequence of their ALS.

    Going further is only speculation. Let’s dive:
    My opinion is that ALS is not really a genetic disease: As people get it at an older age. If it was really a genetic disease like SMA (another motor neuron disease) or Phenylketonuria people would get it as toddler.
    My opinion is that the genetic variants on the human genome like SOD1, FUS or C9orf72 mutations, are only like a constant burden on cells. Scientists call that burden “a cellular stress” (Zelluläre Stressreaktion).

    There is a mechanism called cellular stress response, it’s a coping mechanism. But unfortunately it’s not something as elaborate as the immune system, it’s a basic cellular mechanism that was inherited from our primordial ancestors billion years ago. What it does is that nearly stop all cellular activities in order to enable to endure the stressing event. Think of fungi that become spores and that able to survive thousands of years, before returning to life when conditions have improved. It’s something akin.

    Indeed a cell under cellular stress response cannot not function properly. I think that explains ALS symptoms at least at an early state like failing members. There is a dark side to this coping mechanism: Indeed when the stress is prolonged, the cell dies.

    I believe this is what happens in ALS later stage.

    What can one do before waiting for a therapy?
    It’s odd, but having a BMI at 27 helps people to survive. This had been proven many times. There are even online calorie calculators for pALS, as they need ingesting much more calories than healthy people.
    Some scientists think that changing the diet for a lipid metabolism, could help but that still controversial.
    ALS people who have a PEG live much longer than those who do not.
    And indeed having an healthy life style, no alcohol, etc.

    Let’s keep our fingers crossed.

    (English is not my native tongue)

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