I increasingly believe that the consistently negative results of clinical trials in most degenerative diseases are not because these diseases are difficult to understand, but because most of the scientists who contribute to them are molecular biologists and not doctors or system biology engineers.

*Detail from "Triumph of St. Thomas Aquinas over Averroes" by Benozzo Gozzoli (1420–97)*

Molecular biologists do not care for anatomy of physiology, even worse, they treat the 200 different types of cells in the body as mostly similar. Even if most of neurodegenerative diseases involve anatomical structures that are found only in primates, their animal models are non-primate, and indeed they are astonished that good clinical results in mice do not translate in human beings.

They do not even agree if ALS starts in the brain or in muscles ("dying forward" hypothesis versus "dying backward" hypothesis). Astonishingly several times they "proved" that each of their favorite hypothesis was true and that indeed the competing hypothesis was false.

For ALS alone they implicated more than 120 genes, even if the notion of gene (as a single DNA region which is uniquely implicated in coding a specific strand of RNA) is extremely vague. And they did this before finding that, what was thought as a non coding region (C9orf72) was implicated in ~50% of familial ALS cases. Now C9orf72 is called a gene, so everything is safe again.

Like medieval scholars who discussed how many angels could stand on the tip of a pin, they proposed thousands of small molecules as the causal mechanism for Alzheimer's, Parkinson's, or ALS. The profusion of proposals and the lack of discussion of competing proposals should surely question anyone with a rational mind?

And some authors have stated non-mainstream research proposals were blocked since decades.

This kind of scientist has lost credibility.

There are alternating views, notably by Heiko Braak who says that Parkinson and Alzheimer start with a pathogen invasion in guts and its subsequent progression into the brain. And he and his colleagues provided good evidence for that.

Braak is a medical doctor, but molecular biology scientists did not think much of his findings. Braak is cited only by 0.3% of articles on Parkinson disease.

For a better explanation of why trying to understand something by dissecting it in components and making experiments on isolated components does not help to comprehend how a system works, look at the famous article "Can a biologist fix a radio?"

So in my current view we call different neurodegenerative diseases with different names, but they are mostly the same disease. Whatever neurons are dying in the substantia nigra (Parkinson), primary motor cortex (ALS), or lobes (Alzheimer) it is mainly about neurons dying in the brain. And it is a problem that cannot be solved with molecular biology.

James A. Bashford and colleagues aimed to identify a novel quantitative biomarker related to fasciculations that could monitor patients with amyotrophic lateral sclerosis over time.

Fasciculations are a hallmark of amyotrophic lateral sclerosis. Their presence precedes the onset of muscle weakness. However benign fasciculation syndrome is not considered a prodrome of amyotrophic lateral sclerosis.

The authors have recently developed the Surface Potential Quantification Engine (SPiQE), which is an automated analytical tool designed to detect and characterize fasciculation potentials from resting high-density surface electromyography. SPiQE is capable of analyzing 30-minute recordings, producing simple outputs related to fasciculation frequency, amplitude, inter-fasciculation intervals, and data quality. SPiQE’s analytical pipeline achieved a classification accuracy of 88% when applied to 5318 fasciculation potentials that had been identified manually.

Source: https://backyardbrains.com/

A motor unit comprises the motor neuron cell body, axon, terminal branches, and connecting muscle fibers. Amyotrophic lateral sclerosis leads to a process called chronic partial denervation. This means that as motor units succumb to the disease and die, surviving motor units are instructed to sprout and branch to reinnervate orphaned muscle fibers.

This is an evolutionary, compensatory mechanism designed to maintain muscle power in the face of a reduced motor unit pool. In amyotrophic lateral sclerosis, a reinnervating motor unit steadily acquires new muscle fibers and consequently produces motor unit action potentials of larger amplitude, longer duration, and greater complexity.

However, due to the relentless loss of motor units in amyotrophic lateral sclerosis, this reinnervation process cannot maintain muscle strength indefinitely. A saturation point is reached and muscle fibers consequently atrophy, leading swiftly to clinical weakness. By assessing fasciculation amplitude serially as a surrogate of this reinnervation process, the scientists hoped to gain insight into this process.

It had been suggested that motor unit firing pattern is evidence for motoneuronal or axonal fasciculations; namely, interspike intervals of approximately 5 ms (doublet intervals) provide evidence for axonal firing. Fasciculation doublets have been shown to occur in biceps brachii, vastus lateralis, and tibialis anterior from patients with amyotrophic lateral sclerosis, as well as the gastrocnemius (along with the soleus muscle, the gastrocnemius forms half of the calf muscle) from both patients with amyotrophic lateral sclerosis and benign fasciculation syndrome.

Fasciculation doublets are defined as the occurrence of two almost identical motor unit potentials, presumed to both arise from the same motor unit, with a very short IFI of <100 ms. Shorter inter-fasciculation intervals (5–10 ms) are likely to arise distally in the terminal branches, whereas longer inter-fasciculation intervals (40–80 ms) are thought to originate proximally at the soma.

Faced with the low occurrence rate of doublets during electrical stimulation, the scientists hypothesized that collecting vast numbers of fasciculations would be required to observe IFI peaks in these ranges. In turn, this might help to elucidate the origin of fasciculations in amyotrophic lateral sclerosis.

So in this study, Bashford and colleagues compared amyotrophic lateral sclerosis patients with control subjects who have benign fasciculation syndrome, a condition that is defined by the isolated presence of fasciculations, particularly in muscles of the lower limbs, without evidence of underlying motor neuron degeneration

Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome each underwent up to seven assessments at intervals of 2 months A total of 420 (210 biceps, 210 gastrocnemius) amyotrophic lateral sclerosis and 116 (58 biceps, 58 gastrocnemius) benign fasciculation syndrome recordings were analyzed. Ten biceps recordings from two patients with amyotrophic lateral sclerosis were excluded due to contamination from a Parkinsonian resting tremor

The scientists tested whether muscle weakness in patients with amyotrophic lateral sclerosis influenced the change in fasciculation frequency over time. The scientists divided the data into strong and weak muscles. The scientists divided each muscle into pre-weakness, peri-weakness, and post-weakness groups. This allowed them to assess the chronology of disease by equating these groups to early, middle, and late stages of disease, respectively. This was only possible due to the anatomical specificity of the high-density surface electromyography technique, which is a major strength in this setting.

For biceps, fasciculation frequency in strong amyotrophic lateral sclerosis muscles was 10× greater than the benign fasciculation syndrome baseline, while fasciculation frequency in weak muscles started at levels 40× greater than the benign fasciculation syndrome baseline. Over the 14 months of the study, fasciculation frequency decreased in weak muscles at a rate three times faster than average. This supported the suspicion of the authors that biceps fasciculation frequency was non-linear, first rising steadily from a pre-morbid baseline in strong muscles and subsequently falling as weakness ensued.

Given that there was no significant change in biceps fasciculation frequency over the 14 months of the study in strong amyotrophic lateral sclerosis muscles, Bashford and colleagues hypothesize that the rising phase is slow, perhaps starting many years before clinical weakness. In contrast to biceps, gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles but plateaued in weak muscles.

The most striking implication from these results was the rise and subsequent fall of fasciculation frequency in amyotrophic lateral sclerosis biceps muscles. This non-linear pattern had been previously suggested after statistically modeling fasciculation counts using muscle ultrasound and might explain why a previous surface EMG study of fasciculation frequency did not show a significant linear change over time.

The scientists hypothesize that the two main contributing factors to fasciculation frequency are the size of the affected motor unit pool and the relative degree of hyperexcitability. The size of the viable motor unit pool declines over time in biceps muscles, even while muscles remain strong (albeit at a slower rate than weak muscles). However, it remains unknown what proportion of motor units are affected (and therefore hyperexcitable) at a given stage of the disease.

The decline in fasciculation frequency can be attributed to the relentlessly shrinking motor unit pool. The picture above highlights the proposed model of the interactions between muscle power, size of viable motor unit pool (as assessed by MUNIX), and fasciculation frequency in benign fasciculation syndrome and three stages of disease in amyotrophic lateral sclerosis.

The diagrams depict the dynamic changes in motor unit architecture and relative hyperexcitability (depicted by electric bolts) as a consequence of motor neuron degeneration and motor unit loss.

In benign fasciculation syndrome, there is global hyperexcitability affecting all motor units to a similar degree in the absence of motor neuron degeneration.

In early amyotrophic lateral sclerosis, a subset of motor units are hyperexcitable, motor unit loss has begun and mild–moderate compensatory reinnervation has occurred. Due to the stability of biceps fasciculation frequency in strong muscles over 14 months (at a firing rate ~10 greater than the benign fasciculation syndrome baseline), the rising phase is hypothesized to begin many years before muscle weakness first appears.

It is postulated that towards the latter end of the rising phase, the rate of increase in fasciculation frequency speeds up, so that by the onset of weakness, fasciculation frequency is ~40 the benign fasciculation syndrome baseline.

In the middle stage, the ongoing loss of motor units has promoted extensive re-innervation of surviving motor units, which then become hyperexcitable themselves. This compensatory mechanism leads to fasciculations of greater amplitude and allows muscles to remain strong by staving off muscular atrophy.

However, as a tipping point is reached, these compensatory mechanisms saturate, leading to the onset of muscle atrophy and weakness.

In late amyotrophic lateral sclerosis, the death of the most re-innervated motor units leads to worsening muscle atrophy and weakness. The relentless loss of motor units drives the falling fasciculation frequency. Evidence of doublets with inter-fasciculation intervals in the 20–80 ms range is consistent with the period of motor unit subtypes (fast-slow), supporting a proximal origin of fasciculations at the soma. Throughout all stages of amyotrophic lateral sclerosis and in benign fasciculation syndrome, the degree of hyperexcitability of the lower motor neuron is likely to be driven and/or influenced by descending corticospinal inputs.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Something is wrong with clinical trials for ALS. It seems difficult, if not impossible, to do worse than current experts in the field. The situation is similar for other neurodegenerative diseases such as Alzheimer's or Parkinson's.

Over 700 clinical trials, nearly 500 of which are interventional studies [15], have been conducted over the past 15 years on amyotrophic lateral sclerosis. In the case of Alzheimer's, there have been over 1900 interventional clinical trials and over 2000 of them for Parkinson's disease.

The cumulative cost of these unsuccessful attempts is colossal.

While the average success rate for a phase III clinical trial is over 40%, it is close to zero for neurodegenerative diseases. In fact, there have been more than 80 negative phase III clinical trials in the case of ALS [14].

The public might expect it to be truly unlikely that experts would fail 500 times in a row, or fail 82 times in Phase III, without any success, when the success rate of phase III clinical trials is close to 50%.

Is it an exaggeration to say that this huge number of failures means that not only do we have no idea of ​​the cause and mechanism of this disease, but that experts in charge have no clues about this type of disease?

One of the first paradigms was that since ALS is caused by the death of upper motor neurons (it's the medical definition of ALS), drugs and treatments for stroke should be effective. It shows the thinking of a doctor, not a biologist.

It has been the main paradigm for decades. There is indeed good reason to think that ALS is similar to an extremely slow stroke. In particular, it mainly occurs in the elderly and the symptoms start locally, for example in the muscle of the hand called the thenar. The symptoms then reach increasingly larger areas of the anatomy as the disease develops.

One of the two drugs approved for ALS, Edaravone, is an intravenous drug used to aid healing after stroke. In line with this paradigm that says ALS is a kind of stroke, oxidative stress has long been suspected to be a major factor in the spread of the disease. This is why Rilutek has been approved for ALS.

Then, over the last century, there has been the extraordinary expansion of molecular biology. Biologists then, considerably surpassed physicians in numbers and publications. Biologists became the de-facto experts in ALS.

The promise of molecular biology is indeed revolutionary, and that is to find a simple solution to any non-contagious disease.

It is also a promise of considerable simplicity in tooling, which seems to come out of a kitchen rather than from a sophisticated laboratory. In particular, it becomes possible for biologist students to publish on these subjects a few years earlier than if they were studying medicine.

Molecular biology involves a complete paradigm shift in the way we think about ALS disease.

The brains, the nerves and the muscles are forgotten. The cells, whose internal mechanisms are however still largely unknown at the end of the XX century, are rejected as irrelevant in a process of thought which is centered on the translation of the genome in proteins.

The blindness towards medicine, is however difficult to understand for neurodegenerative diseases, because for example reactive astrocytes have been repeatedly identified as a component of senile amyloid plaques in the cortex of patients with Alzheimer's disease. from 1988 [9-12]. But not long ago, 30 years later, the theory implicating amyloid plaques in Alzheimer's disease was still the dominant theory.

This may correspond to what was known at the time, as astrocytes and microglia were then considered almost useless. This is, however, something astonishing to say, even at the end of the 20th century, since these cells clearly constitute a large part of the matter of the brain and the spine.

It started off well for the application of cell biology in neurodegenerative diseases, with an apparent success in 1998, when mutations in the SOD1 gene were implicated in familial ALS. Unfortunately, it quickly became clear that SOD1 mutations only affect a small number of familial cases of ALS and they presented a great diversity with a life expectancy varying from one year in severe forms to 10 years or more in other less dangerous mutations.

Although the vast majority of articles on ALS concern SOD1, mutations in SOD1 therefore appear to be an epiphenomenon in the case of ALS, both because of their very low frequency but also for the diversity of phenotypes.

The main cause of familial ALS was not found until 2011, 20 years after promises from like those of the human genome project. Mutations in C9orf72 create repeats motifs in some proteins. Geneticists had been investigating familial ALS for about 30 years, and the lack of progress raised concerns. C9orf72 is not a gene, it is an area that was considered non-coding until then, hence the difficulty in using molecular biology tools.

Strangely enough, these pattern repeats are also present in everyone, but more pronounced in the elderly. They are also present in other diseases. So it seems that the number of repetitions could involve different diseases.

Molecular biology has proposed more than a hundred genes as participating in the etiology of ALS and has proposed thousands of drugs and at one point scientists started to be reluctant to incriminate even more genes in ALS (or Alzheimer's, etc.).

Thus, for scientists who had decided to pursue a career in molecular biology and who thought they were in an impasse, there was a strong temptation to turn towards translation and post-translational modifications of proteins.

We were then inundated with studies claiming that this or that protein was poorly translated, poorly conformed or poorly localized in the cell. The subject of misfolded proteins even created small wars between biologists (Tauiste against Baptiste). The problem is that most of these proposed proteins are found in most neurodegenerative diseases, Tau, TDP-43, etc [1]. So they do not seem specific to ALS, Alzheimer's or Parkinson's. If they are not specific, how can they be causative of one, but not other neurodegenerative diseases?

There are however alternative views among scientists working in the field of ALS, one is that ALS starts in muscles, not in the brain. This hypothesis has been both * proven and disproved * on several occasions, which seems very confusing from a non-specialist's point of view. But anyway this hypothesis does not explain what would cause the muscle disease, it only pushes the explanation of this muscle wasting, away to future works.

If we think globally, like a doctor, there are two common reasons for cells to die (be it muscle cells or upper motor neurons). There is no need for extremely sophisticated explanations for this.

Either their blood supply is faulty (see the similarity to stroke above) or the cellular metabolism is faulty (hence the appearance of reactive stress).

It seems that articles on a defective metabolism are quite rare, but they could be found, here are examples [7-8, 13]. Some articles have even blamed the use of methionine sulfoximine (MSO) in a now abandoned flour bleaching process [8] or other environmental contaminants as contributing factors to ALS. It is surprising that although there have been many publications on these two topics, no clinical trial has tried drugs linked to metabolic dysfunction.

For example, clinical trials could study: * MAO-B inhibitors [2], * Methionine sulfoximine (MSO) which dramatically extended the lifespan of a SOD1 G93A mouse model for ALS. [3] * Pathological inhibition of glutamine synthetase (GS). In the brain, GS is exclusively localized in astrocytes where it is used to maintain the glutamate-glutamine cycle, as well as nitrogen metabolism. Changes in GS activity have been identified in a number of neurological conditions [4]. * Methionine sulfoximine (MSO), a well-characterized glutamine synthetase inhibitor, is a convulsant, particularly in dogs, but shows significant therapeutic benefits in animal models for several human diseases [5, 6] * But also many other drugs related to the brain and spine metabolism.

[1] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/

[2] https://pubmed.ncbi.nlm.nih.gov/32852645/

[3] https://pubmed.ncbi.nlm.nih.gov/28323087/

[4] https://pubmed.ncbi.nlm.nih.gov/27885636/

[5] https://pubmed.ncbi.nlm.nih.gov/28292200/

[6] https://pubmed.ncbi.nlm.nih.gov/24136581/

[7] https://pubmed.ncbi.nlm.nih.gov/7148401/

[8] https://pubmed.ncbi.nlm.nih.gov/10052866/

[9] https://www.ncbi.nlm.nih.gov/pubmed/3196922/

[10] https://www.ncbi.nlm.nih.gov/pubmed/2531723/

[11] https://www.ncbi.nlm.nih.gov/pubmed/2808689/

[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996928/

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063041/

[14] https://clinicaltrials.gov/ct2/results?cond=Amyotrophic+Lateral+Sclerosis&term=&cntry=&state=&city=&dist=&Search=Search&phase=2&phase=3

[15] https://clinicaltrials.gov/ct2/results?cond=Amyotrophic+Lateral+Sclerosis&age_v=&gndr=&type=Intr&rslt=&Search=Apply

Quelque chose ne va pas dans les essais cliniques sur la SLA. Il semble difficile, voire impossible de faire moins bien que les experts actuels du domaine. La situation est similaire pour des maladies neurodégénératives comme Alzheimer ou Parkinson.

Plus de 700 essais cliniques, dont près de 500 sont des études interventionnelles [15], ont été menés depuis 15 ans sur la sclérose latérale amyotrophique. Dans le cas d’Alzheimer, il y a eu plus de 1900 essais cliniques interventionnels et plus de 2000 d’entre eux pour la maladie de Parkinson.

Le coût cumulé de ces essais infructueux est colossal.

Alors que le taux de réussite moyen d'un essai clinique de phase III est supérieur à 40%, il est proche de zéro pour les maladies neurodégénératives. En effet il y a eu plus de 80 essais cliniques de phase III négatifs dans le cas de la SLA [14].

Cela semble un nombre énorme et impressionnant, et le public pourrait s'attendre à ce qu'il soit vraiment improbable que des experts échouent 500 fois à la suite, ou qu'ils échouent 82 fois en phase III, sans le moindre succès, alors que le taux de réussite des essais clinique de phase III est proche de 50%.

Est-il exagéré de dire que ce nombre énorme d'échecs signifie que non seulement nous n'avons aucune idée de la cause et du mécanisme de cette maladie, mais nos experts ne sont pas compétents sur ce type de maladie.

L'un des premiers paradigmes était que, comme la SLA est due à la mort de motoneurones supérieurs (définition médicale de la SLA), les médicaments et les traitements pour l'AVC devraient être efficaces. Cela montre une réflexion de médecin, pas de biologiste.

Ça a été le paradigme principal pendant des décennies. Il y a en effet de bonnes raisons de penser que la SLA est une sorte d’accident vasculaire cérébral extrêmement lent. En particulier, cela se produit principalement chez les personnes âgées et les symptômes commencent de façon localisée, par exemple au niveau du muscle de la main nommé thénar. Les symptômes atteignent ensuite des zones de l’anatomie de plus en plus importantes au fur et à mesure du développement de la maladie

L'un des deux médicaments approuvés pour la SLA, Edaravone, est un médicament intraveineux utilisé pour aider à la guérison après un AVC. Dans la ligne de ce paradigme qui dit que la SLA est une sorte d’AVC, on soupçonnait depuis longtemps que le stress oxydatif était un facteur majeur de propagation de la maladie. C'est pourquoi Rilutek a été approuvé.

Puis, au cours du siècle dernier, il y a eu l'expansion extraordinaire de la biologie moléculaire. Les biologistes surpassent les médecins dans les effectifs et dans les publication.

La promesse de la biologie moléculaire est en effet révolutionnaire, c’est de trouver une solution simple à toute maladie non contagieuse.

C’est une promesse aussi de simplicité considérable dans l’outillage, qui semble sortir de chez un cuisiniste plutôt que d’un laboratoire sophistiqué. En particulier il devient possible à des étudiants de publier sur ces sujets quelques années plus tôt que s’il s’agissait de médecins.

La biologie moléculaire implique un changement de paradigme complet dans la façon de penser la maladie.

Les cerveaux, les nerfs et les muscles sont oubliés, les cellules, dont le fonctionnement est pourtant encore largement inconnu, à la fin du XX siècle, sont rejetées car non pertinents dans un processus de pensée qui est centré sur la translation du génome en protéines.

Les scientifiques reviennent pourtant maintenant de ce genre d'explications qui se sont finalement avérées le plus souvent infructueuses.

Ces cécités envers la physiologie ou même la médecine, est pourtant difficile à comprendre pour les maladies neurodégénératives, car par exemples les astrocytes réactifs ont été plusieurs fois identifiés comme un composant des plaques amyloïdes séniles dans le cortex des patients atteints de la maladie d'Alzheimer dès 1988 [9-12]. Or il y a peu, 30 ans plus tard, la théorie impliquant les plaques amyloïdes dans la maladie d'Alzheimer, était encore la théorie dominante.

Cela peut correspondre à ce qui était connu à l'époque, car les astrocytes et les microglies étaient alors considérés comme presque inutiles. C’est cependant quelque chose d'étonnant à affirmer, même à la fin du XX siècle, puisque manifestement ces cellules constituent une grande partie de la matière du cerveau et de la colonne vertébrale.

Cela avait pourtant bien commencé pour l’application de la biologie cellulaire dans les maladies neurodégénératives, avec un grand succès apparent en 1998, quand des mutations du gène SOD1 ont été impliquées dans la SLA familiale. Hélas il est vite apparu que les mutations SOD1 ne concernaient qu'un petit nombre de cas familiaux de SLA et qu'elles présentaient une grande diversité avec une espérance de vie variant d'un an dans les formes sévères à 10 ans ou plus dans des mutations moins dangereuses. Bien que la très grande majorité des articles sur la SLA concerne SOD1, les mutations de SOD1 semblent donc un épiphénomène dans le cas de la SLA, à la fois pour leur très faible fréquence mais aussi par la diversité des phénotypes.

La principale cause de la SLA familiale n'a été trouvée qu'en 2011, 20 ans après les promesses de la biologie cellulaire, des mutations dans C9orf72 créent des répétitions dans certaines protéines. Cela faisait une trentaine d’année que les biologistes investiguaient la SLA familiale, et le manque de progrès faisait craindre que l’on ne pourrait éclaircir ce problème. C9orf72 n’est pas un gène, c’est une zone qui était réputée non-codante jusque-là, d’où la difficulté à utiliser les outils de biologie moléculaire.

Un peu étrangement ces répétitions de motifs sont également présentes chez tout le monde, mais plus prononcées chez les personnes âgées. Elles sont également présentes dans d'autres maladies. Ainsi il semble que le nombre de répétitions pourrait impliquer différentes maladies.

La biologie moléculaire a proposé plus d’une centaine de gènes comme étiologie de la SLA participante et a proposé des milliers de médicaments et à un moment donné, les scientifiques commencent à être réticents à incriminer encore plus de gènes dans la SLA (ou Alzheimer, etc.). Ainsi, pour les scientifiques qui avaient décidé de faire carrière en biologie moléculaire et qui se pensaient face à une impasse, la tentation était forte de pivoter vers la traduction et les modifications post-traductionnelles des protéines.

Nous avons alors été inondés d'études affirmant que telle ou telle protéine était mal traduite, mal conformée ou mal localisée dans la cellule. Le sujet des protéines mal repliées a même créé de petites guerres entre biologistes (Tauiste contre Baptiste). Le problème est que la plupart de ces protéines proposées sont trouvées dans la plupart des maladies neurodégénératives, Tau, TDP-43, etc [1]. Ainsi elles ne semblent pas spécifiques de la SLA, d’Alzheimer ou de Parkinson.

Il y a des points de vue alternatifs chez les scientifiques travaillant dans le domaine de la SLA, l'un est que la SLA commence dans les muscles, pas dans le cerveau. Cette hypothèse a été à la fois * prouvée et réfutée * à plusieurs reprises, ce qui semble très confus du point de vue d’un non-spécialiste. Mais de toute façon cette hypothèse n’explique pas ce qui causerait la maladie musculaire, elle ne fait que repousser l’explication de ce dépérissement musculaire vers des travaux futurs.

Si nous raisonnons de manière globale, à la façon d'un médecin, il y a deux raisons communes pour que les cellules meurent (que ce soit celles des muscles ou encore les motoneurones supérieurs). Il n’y a pas besoin d’explications extrêmement sophistiquées pour cela.

Soit leur approvisionnement en sang est défaillant (voir la similitude avec l'AVC plus haut), soit le métabolisme cellulaire est défectueux (d'où l’apparition d’un stress réactif).

Il semble que les articles sur un métabolisme défectueux soient assez rares, mais certains discutent que l'ammoniac pourrait être un facteur de la SLA [7-8, 13]. Certains articles ont même incriminé l'utilisation de la méthionine sulfoximine (MSO) dans un processus de blanchiment de la farine, aujourd’hui abandonné [8] ou encore d'autres contaminants environnementaux comme étant des facteurs de la SLA. Il est étonnant que, bien qu'il y ait eu de nombreuses publications sur ces deux sujets, aucun essai clinique n'ait essayé des médicaments liés au dysfonctionnement du métabolisme.

Par exemple, les essais cliniques pourraient étudier: * Les inhibiteurs MAO-B [2], * La méthionine sulfoximine (MSO) qui a considérablement prolongé la durée de vie d'un modèle murin SOD1 G93A pour la SLA. [3] * L’inhibition pathologique de la glutamine synthétase (GS). Dans le cerveau, la GS est exclusivement localisée dans les astrocytes où elle sert à maintenir le cycle glutamate-glutamine, ainsi que le métabolisme de l'azote. Des modifications de l'activité de la GS ont été identifiées dans un certain nombre de conditions neurologiques [4]. * La méthionine sulfoximine (MSO), un inhibiteur bien caractérisé de la glutamine synthétase, est un convulsif, en particulier chez le chien, mais présente des bénéfices thérapeutiques significatifs dans des modèles animaux pour plusieurs maladies humaines [5, 6] * Mais aussi beaucoup d'autres médicaments potentiels.