ALS News Today Forums Forums ALS Progress Research Topics An excellent review of the disease mechanisms of ALS

  • An excellent review of the disease mechanisms of ALS

    Posted by dagmar-munn on July 2, 2021 at 12:32 pm

    I wish something like this had been available 11 years ago when I was diagnosed with ALS. I could find only vague descriptions and outdated opinions of how ALS occurs in the body.

    This recent article from the ALS Association provides an excellent short-hand description of the process of ALS. I believe this is helpful for both the newly diagnosed and ongoing cases (like myself).

    Here are highlights I pulled from the article. You can read the full text here:

    ALS is a heterogeneous disease, meaning that there are many diverse ways that disease can occur. It is very likely that more than one disease process is occurring in a person living with ALS. From years of research, scientists have identified various disease processes involved in ALS.
    Axon Structure and Dynamics: Active transport along the extensive axons of motor neurons conveys newly made materials to even the farthest-reaching nerve endings and needed nutrients back to the cell body. Motor neurons may be particularly vulnerable to any genetic defect or cellular insult that impedes axon transport.
    Cell Death: Apoptosis and Necrosis: halting apoptosis when it is producing a degenerative change in the nervous system is now a prime goal for researchers trying to design effective treatments for ALS as well as for other neurological disorders.
    Mitochondria: changes in the mitochondria can be detected before one can find a physical change, such as hind limb weakness in mice. In addition, mitochondria show damage early in the ALS disease process, a finding that is leading researchers to study this cell component intensively.
    Glutamate: Prolonged excitation of the nerve cell can occur from too much glutamate, which is toxic. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed. The first approved specific treatment for ALS is riluzole, a drug that modulates glutamate.
    Inflammation: There is increasing evidence that neuroinflammation accompanies the death of motor neurons in ALS. However, evidence so far does not support that ALS is an autoimmune disease. The inflammatory process apparently is a reaction to the death of the cells, and not the instigator.

    Was this article helpful to you? What are your thoughts about the different mechanisms listed? Which one do you think researchers should be focusing on?

    jean-pierre-le-rouzic replied 2 years, 2 months ago 1 Member · 1 Reply
  • 1 Reply
  • jean-pierre-le-rouzic

    July 2, 2021 at 9:42 pm

    Thanks Dagmar for researching some simple and easily comprehensible text on what is ALS, but I find this specific text extremely imprecise and confusing about what scientists know about ALS. And it lacks to tell about some areas, for example the genetic background.

    > ALS is a heterogeneous disease,
    There is no real diagnosis of ALS. It’s only a differential diagnostic: When one has motor troubles and muscle wasting, and when it’s impossible to diagnose another disease, then someone is told they have ALS. Is there really a single disease named ALS? If there is no clear single ALS disease then saying it’s a heterogeneous disease is true but not very helpful.

    > Axon Structure and Dynamics
    Most ALS scientists think along the “dying forward” hypothesis which postulates that ALS (like Parkinson or Alzheimer) starts in the brain, specifically in the motor area where are the bodies of upper motor neurons. If that’s true, and it’s the most common statement, then it has nothing to do with axons, and specially with axons of lower motor neurons.

    The transport mechanism of motor neurons has been implicated by some scientists, but other have different ideas.

    > Cell Death … is now a prime goal for researchers trying to design effective treatments for ALS
    Seriously how can someone write such a sentence? If motor neurons die, then in 2021 state of art with no regeneration in sight, it’s the end of the game. There would be no possibility to revive them.

    But we know that in ALS motor neurons (and other nervous cells) activate several mechanisms to cope with cellular stress. Those mechanisms like UPR (unfolded protein response) effectively stop the cell, and put it in a kind of “freezed” state in order to protect it from some cellular stress, and if the cellular stress diminishes then the cell starts working again. Scientists are not able to have a common ground about if ALS is a disease of upper motor neurons, other neuronal cells (their importance was neglected until the last 10 years, even though they are much more numerous than neurons) or lower motor neurons. Some scientists even think that ALS starts at the neuromuscular junction (extreme axonopathy). There are even neurodegenerative diseases that starts in muscle (virus that use the enterograde transport mechanism). Other scientists like Braak think this kind of disease starts in guts.

    > changes in the mitochondria can be detected before one can find a physical change.
    Again a weird statement. It’s trendy to point to “mitochondria” for a lot of chronic diseases, but mitochondria are minuscule, highly dynamics structures that can multiply when there is a need (for example exercise) and be recycled when there is no need. They also move a lot.
    Beside mitochondria are minuscule structures that can’t be seen with an ordinary microscope, there are thousands of them in a single cell.
    At least in humans, no changes can be detected in mitochondria’s number or localization before symptoms appears, because it would involve making dozen of biopsies of motor neurons on a healthy, and nobody do that even for research. And what would be the medical value of such sample?

    > glutamate as a destructive factor in ALS
    Glutamate is indispensable for our nervous system. More accurately excitotoxicity is thought to be involved in ALS since one hundred year, because most theories about ALS’ etiology are influenced by stroke mechanisms. When glutamate is not recycled correctly at the nervous junction then calcium enters and excess calcium kill cells. But on ALS scientific literature you can find many articles that prove AND many other that disprove this hypothesis. And there are thousand of other similar hypotheses about ALS etiology, the reality is that no one knows.

    > There is increasing evidence that neuroinflammation accompanies the death of motor neurons in ALS.
    Inflamation is a weasel word, it is not specific, neither the word “accompanies”. Like “mitochondria” it’s a magic word which is thrown in conversation when we have no clues about a disease. To be more specific we would have to talk about our various immune systems (innate, adaptive, complement) and their signaling mechanisms like cytokines.
    There are scientists like Dr Appel who think that some parts of the immune systems are involved in ALS. These scientists generally tell that the Blood-Brain barrier let the immune system invade the CNS. But the BBB is also some magic word, as actually it’s just a layer of cells around each axon of the lower motor neurons or around the blood vessels in the brain. It’s not (as people commonly imagine) some kind of membrane. So far this has not translated in successful clinical trials. Other scientists have their own pet theories, nobody knows what is correct.

    In conclusion:
    Unfortunately scientists have no clues about ALS and for other neurodegenerative diseases like Alzheimer or Parkinson or some dementia. I think they look at the wrong place.
    In the 1990 there was a new generation of young researchers who where attracted by molecular biology. Yet this area of research had been remarkably sterile in general in the last 30 years.

    If you look at which drugs where used in the 750+ clinical trails, there is no common theme, the drugs used are extremely different and it is rare that the principal investigators write about their mechanism of action. Often the same drug is repetitively tried (like Memantine) even when it failed several times previously. It’s a waste of resources.

    What we need are medical doctors who think about healing ALS people, we do not need academics who just want to publish quick and dirty papers full of academic verbiage because that’s the way they get a good career.

    Looking after molecular events in motor neurons is not the smartest thing we did in ALS.

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