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.

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*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 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 analysing 30-min 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 fibres. 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 muscles fibres.

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 fibres 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 process of reinnervation cannot maintain muscle strength indefinitely. A saturation point is reached and muscle fibres 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 the 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 collection of 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 the presence of 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 modelling 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 remained 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 highlight 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.

Une combinaison de deux médicaments expérimentaux, désignée par le sigle « AMX0035 » semble ralentir le déclin des patients atteints de sclérose latérale amyotrophique, une maladie souvent connue par son abréviation « SLA » ou encore maladie de Charcot. enter image description here La SLA détruit les cellules nerveuses qui contrôlent les mouvements musculaires. Les patients deviennent généralement handicapés. On distingue généralement les patients à progression lente (avec une meilleure espérance de vie) de ceux qui ont une progression rapide. Les patients ayant une progression rapide meurent dans les cinq ans suivant leur diagnostic.

L'essai CENTAUR de 137 personnes atteintes de SLA a été mené dans 25 centres médicaux de premier plan aux États-Unis par le biais du consortium Northeast ALS (NEALS). Il s'est achevé fin 2019, sa durée de six mois portait sur 137 patients atteints d'une forme à évolution rapide de la maladie.

L'essai clinique a révélé que les patients qui recevaient des doses quotidiennes de cette combinaison de deux médicaments avaient connu une moindre progression de leur maladie. L’étude est parue dans le numéro du 3 septembre du New England Journal of Medicine.

Les participants ont été randomisés dans un rapport de 2: 1 pour recevoir du phénylbutyrate de sodium – taurursodiol (3 g de phénylbutyrate de sodium et 1 g de taurursodiol, administrés une fois par jour pendant 3 semaines puis deux fois par jour) ou un placebo.

Le Dr Sabrina Paganoni a déclaré que la différence était modeste mais significative pour les patients. Elle est l'auteur principal et chercheuse au Sean Healey & AMG Center for SLA à Mass General et à la Harvard Medical School.

En effet les deux médicaments actuellement mis sur le marché pour la SLA ont une efficacité très faible. Aucun de ces deux médicaments (Riluzole et Edaravone) n’est aussi efficace que la nouvelle proposition « AMX0035 ». Elle semble aussi bien tolérée ce qui est rare dans le cas des maladies neurodégénérescentes.

Les résultats sont cependant loin de permettre de recouvrer leur mobilité. Mais même ainsi, Paganoni est "convaincu que nous sommes au début d'une nouvelle ère dans la découverte du traitement de la SLA".

"Il y a un grand espoir pour un traitement modificateur de la maladie", a ajouté Tania Gendron, qui étudie les maladies neurodégénératives à la clinique Mayo de Jacksonville et n'a pas participé à l'étude. "Dans les prochaines années, je pense qu'il y aura de grandes découvertes."

Pendant des décennies, le seul médicament approuvé pour la SLA était le Riluzole (Rilutek), qui est sur le marché depuis 1995 et qui prolonge la vie des patients. Puis en 2017, l'Edaravone, qui aide certains patients à conserver leur fonction plus longtemps, a lui aussi reçu une autorisation de commercialisation.

AMX0035 fonctionne en protégeant les cellules nerveuses de deux types de dommages qui sont les caractéristiques de la SLA. Et dans l'étude, cela a produit un avantage, même si de nombreux patients prenaient déjà du riluzole et de l'édaravone.

Il semble que les nouveaux et les anciens médicaments agissent tous de manière différente pour ralentir la maladie, a déclaré Paganoni. "Nous pensons que nous aurons finalement besoin d'une combinaison de traitements pour lutter efficacement contre la SLA."

D'ordinaire, une étude de taille plus importante serait nécessaire avant que la FDA n’envisage d'approuver le médicament. Mais l'association Américaine ALSA et le groupe de patients « I AM ALS » ont uni leurs forces pour demander à la FDA de faire une exception.

"Dans la SLA, un essai clinique de grande taille prendrait probablement environ trois ans", a déclaré Neil Thakur, chef de mission de l'ALSA. "Et donc la question pour toute la communauté est de savoir ce que nous gagnerions avec cette étude de trois ans?"

L'Association ALS a aidé à financer la recherche sur l'AMX0035 et a un intérêt financier dans son succès. La principale préoccupation du groupe, cependant, concerne les patients qui ne vivront pas assez longtemps pour attendre une autre étude, a déclaré Thakur.

«C'est pourquoi nous pensons que la meilleure chose à faire pour la communauté est de rendre ce médicament disponible plus tôt et de permettre à tout le monde de l'avoir comme option de traitement dès que possible», a-t-il déclaré.

AMX0035 a emprunté une voie très inhabituelle vers l'autorisation de mise sur le marché.

Il a été développé par Amylyx, une petite entreprise fondée par un couple d'étudiants, Josh Cohen et Justin Klee, qui sont encore dans la vingtaine. Les deux hommes travaillaient tard une nuit dans le bureau de la société à Cambridge, dans le Massachusetts, lorsqu'ils ont appris les résultats de l'étude sur la SLA.

"Lorsque les statisticiens ont appelé, vous pouviez entendre toute les employés de la société applaudir en arrière-plan", a déclaré Cohen. Mais leur exaltation était mélangée à un sens des responsabilités, a déclaré Klee.

"Bien que ces résultats soient excellents, ce n'est pas encore annonciateur d’un remède, et donc nous et d'autres membres de la communauté entière devons continuer à avancer jusqu'à ce que nous obtenions de véritables remèdes", a-t-il déclaré.

Des patients ont déclaré sur des forums Internet, avoir reçu de leur neurologue une prescription correspondante à l'AMX0035.

L’essai PEGASUS est en cours pour évaluer l’innocuité, la tolérabilité et l’activité d’AMX0035 chez les patients présentant une déficience cognitive légère tardive ou une démence précoce due à la maladie d’Alzheimer.

PXT864 is an example of a repurposed drug combination. It uses baclofen and acamprosate, taken twice a day. Baclophen is a derivative of γ-aminobutyric acid, aka GABA, and acts as a GABA-B receptor agonist. It is used as a muscle relaxant to treat spasticity, for example in cerebral palsy and multiple sclerosis. Acamprosate is a drug of unclear mechanism of action, which is used to treat alcohol dependence.

While no double blind phase I/II/III clinical trial has tested PXT864, two small studies tested it for Alzheimer disease in 2013 to 2015. There was also a publication in 2015 in Nature's Scientific reports about effects of PXT864 on a rat model of Parkinson disease (6-OHDA). They used stereotaxic injection rat model to assess the efficacy of the combination in vivo in 6-OHDA rats. This model offers the benefit that each animal serves as its own control.

In a new publication PXT864 activity was assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model of ALS, glutamate application induced an accumulation of TDP-43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti-TDP-43 aggregation effect was also confirmed in a cell line expressing TDP-43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

Testing in-vitro is cheap with respect to test with animal models, and it is well known that no animal model of neurodegenerescent diseases reflects what is happening in humans.

Typical of biotech players, Pharnext, which began in 2007, has had its struggles. It is deeply unprofitable but the driving force behind Pharnext’s strategy is its founder, Daniel Cohen, who led the team that mapped the human genome in the 1990s, and now functions as his company’s chief scientist.

Nevertheless baclofen and acamprosate are two common drugs, so this might interest many ALS patients. However both drugs have strong and indesirable side effects.

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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.

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intra-thecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. Unfortunately it did not went well for the patients, but there are many interesting observations in this article. One of them is that one of the patient had an infection of Borrelia burgdorferi, a tick-borne spirochete bacterium also responsible for causing Lyme disease, which was discovered during the course of the disease.

Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity.

Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period.

Patient 1

During the month of February 2017, Patient 1, a 22-year-old man, began to notice weakness in his left leg. He had the same SOD1 missense mutation (SOD1-A5V) as his mother, who had died from ALS at the age of 45 years. In March 2017, his slow vital capacity was 100% of the predicted value, and his ALSFRS-R score was 42. The flexion strength in his left hip was MRC grade 3, which indicated that he could move the limb against gravity. He could not bear full weight on his left heel or toes though.

On July 19, 2017, he received a single intrathecal infusion of 4.2×1014 vector genomes of AAV-miR-SOD1 along with an intravenous bolus of methylprednisolone (1.0 g); the latter was repeated the following day. Oral prednisone (at a dose of 60 mg per day) was then initiated, with planned tapering during a 4-week period. At that time, there was no plantar flexion or dorsiflexion in the left ankle ; the left knee flexion and extension could move only with gravity eliminated; The strength of the right leg and both arms was normal, as were sensory function and cognition.

Three weeks after the infusion, he had transient tingling in both hands, and 1 week later, he reported having a feeling of painful “electric shocks” in his left foot. The prednisone dose, which had been tapered to 10 mg per day, was increased to 30 mg.

Twenty-four weeks after treatment (46 weeks after the onset of ALS symptoms), the patient’s ALSFRS-R score was reduced to 38 from the baseline level of 42. The loss of strength in the left leg continued.

But at 12 months after treatment (nearly 18 months after the onset of ALS symptoms), the patient had transient improvement in the strength of his right leg, and could propel himself in a wheelchair using the right leg. However vital capacity was further reduced to 21% of the predicted value. At 14 months, he regained the ability to extend and flex the fingers of the left hand, a function that had been absent for the previous 20 weeks.

Lymphocytic meningoradiculitis, also known as Bannwarth syndrome, is a neurological disease characterized as intense nerve pain radiating from the spine. The disease is caused by an infection of Borrelia burgdorferi, a spirochete bacterium.

The patient died of respiratory arrest 15.6 months after the initiation of treatment and 20.5 months after the onset of ALS symptoms. The AAV-miR-SOD1 viral genome was detected in the cervical and lumbosacral spinal cord parenchyma. As compared with a baseline SOD1 level of 120 ng per milliliter in the CSF, the level was 102 ng per milliliter at 8 weeks and 120 ng per milliliter at 41 weeks

There were a loss of motor neurons in the cervical, thoracic, and left lumbosacral spinal cord but relative sparing of motor neurons in the right lumbosacral spinal cord.

The cortical ribbon in the primary motor–sensory cortex was moderately gliotic. Glial scar formation is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system.

Pyramidal neurons had pyknotic nuclei and hypereosinophilic cytoplasm, findings that were consistent with acute hypoxic–ischemic injury. Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Pyknosis, is the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis.

The authors hypothesized that intrathecal infusion of this viral vector can trigger an adverse inflammatory response, as has been reported in some studies after the intravenous administration of AAV9 in animals.

The scientists cannot conclude that suppression of SOD1 played a role in his clinical course, since such improvements in function may have reflected recovery from meningoradiculitis.

Patient 2

For patient 2, during the year before therapy, his functional status had been stable, with ALSFRS-R scores averaging close to 28. For a year before treatment, his slow vital capacity had ranged from 42 to 58% of the predicted value;

As meningora-diculitis developed after treatment in Patient 1 and they suspected some relation between the two events, the scientists aimed to suppress B-cell activity and T-cell function with rituximab (at a dose of 375 mg per square meter of body-surface area), which was initiated in late August 2018 in weekly intravenous infusions for 3 weeks and with intrave-nous methylprednisolone (at a dose of 125 mg before each dose of rituximab and 1 g on the day of AAV-miR-SOD1 infusion).

Beginning at the initiation of study treatment, the patient began receiving daily oral sirolimus (6 mg). The day after treatment, oral prednisone (0.5 mg per kilogram of body weight) was initiated; sirolimus and prednisone were continued for 6 months.

On September 17, 2018, the patient received an intrathecal infusion of 4.2×1014 vector genomes of AAV-miR-SOD1.

On the day after treatment and at weeks 12 and 17, he received intra-venous immune globulin (at a dose of 0.4 mg per kilogram) in response to a decrease in the serum IgG to a level of less than 700 mg per deciliter, which had been induced by rituximab.

60 weeks after treatment, the ALSFRS-R score was 24, signifying worse overall function.
At 65 weeks after therapy, the slow vital capacity score value was 62% .

In contrast to the clinical course of Patient 1, the immuno-suppressive regimen in Patient 2 blunted the generation of neutralizing antibodies, antiviral antibodies, and T-cell response to the viral capsid. As of May 18, 2020, his disease course was stable, with a functional measure of 24 at 90 weeks after treatment. A course that could be typical of the slow disease progression in patients with his SOD1 genotype, so no clinical conclusions can be made about the treatment effects.

Conclusion

It is very important for the scientific knowledge acquisition process to publish failures. This study is in this respect important, but it is a quite rare publication that describes also other aspects of the story. If intrathecal genetic therapies incur an increased risk of a Borrelia burgdorferi based disease, this is an extremely important fact.

The article discussed here is not related to neurodegeneration diseases, it discusses about heart failure, however it might have implications for ALS. While most ALS targeting therapies might aim at reducing TDP-43 aggregates (and similar protein aggregates in other neurodegenerative diseases), humans are indeed more than bags of identical cells, they are first living because they are composed of a multitude of physiological systems that interact to maintain homeostasis. So even if a therapy was invented that would efficiently remove TDP-43 aggregates, ALS patients would still be unable to recover health as motor neurons do not rejuvenate nor are replaced with newer cells. As this heart failure treatment improves heart muscle cells, it should also to some degree improve motor neuron cells. This article is also interesting as it mentions some drugs that are discusses ALS online internet forums, such as glutathione, N-Acetyl Cysteine (NAC) and Glycine.

This article explains precisely how some muscle cells seem to rejuvenate when a specific peptide is administrated. Very roughly: With this peptide, metabolism is rejuvenated at cellular level, so cells can use more energy, something which is clearly lacking in ALS cells which are characterized by hypermetabolism. Humans produce and consume about 65 kg of ATP every day. Because ATP cannot be stored, it is critical that the rate of ATP synthesis matches the rate of ATP consumption. The primary role of mitochondria is the generation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) using macromolecular complexes that form the electron transport chain.

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Mitochondrial dysfunction is one of the hallmarks of aging. While mitochondria generate the bulk of cellular ATP, they are also the major source of reactive oxygen species (ROS) in most cells. ROS are sub-products inherent to ATP metabolism.

Aging is the strongest risk factor for cardiovascular diseases. It is also accompanied by a decline in cardiac function, especially diastolic dysfunction and hypertrophy of the left ventricle and left atrium. The heart is rich in mitochondria and has a high metabolic demand; therefore, it is highly susceptible to oxidative damage and the effects of mitochondrial dysfunction. Increasing evidence suggests that mitochondrial oxidative stress and mitochondrial dysfunction play critical roles in cardiovascular diseases and cardiac aging.

The mitochondrial-targeted tetrapeptide SS-31 (elamipretide), is a pharmacologic intervention that selectively concentrates in mitochondria, suppressing mitochondrial ROS and increasing skeletal muscle ATP production. Elamipretide (also named SS-31, MTP-131, Bendavia) is sold by Stealth BioTherapeutics, Newton, Massachusetts. It is a water-soluble, aromatic-cationic mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane and associates with cardiolipin to restore mitochondrial bioenergetics

it has not been established whether delivering such interventions in later life can rescue pre-existing mitochondrial and cardiac dysfunction. In this study, the authors demonstrate that mitochondrial-targeted interventions can improve mitochondrial function and reverse pre-existing cardiac dysfunction in old mice.

To determine the effects of SS-31 treatment on cardiac function in old mice, the scientists treated 24-month-old mice with the SS-31 peptide or saline control and examined cardiac function by echocardiography after 4 and 8 weeks of treatment.

SS-31 treatment was effective in aged hearts with pre-existing mitochondrial dysfunction but had little effects in young hearts with normal functioning mitochondria.

The authors acknowledge that the persistence of SS-31 induced functional benefit varied between individual mice. Other studies have reported negative effects of targeting mitochondrial ROS. In another study, suppression of mitochondrial ROS in mice resulted in impaired macrophage bactericidal activity.

However not everything is rosy, elamipretide is known since quite some time and had been tested in several different diseases. Recently it did not meet expectations stemming from promising early trial results in patients with primary mitochondrial myopathy (PMM), data from a Phase 3 (NCT03323749) trial show.

Stress granules are believed to play a critical role in modulating gene expression programs in response to environmental and nutrient stresses. However, it has been unclear how changes in cellular activity regulate stress granule formation and composition. The authors of a recent article, shown that Sam1 is recruited to yeast stress granules in response to a specific nutrient stress.

S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM-e is produced and consumed in the liver. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase.

The scientists found that the product of Sam1, AdoMet, regulates stress granule formation in both yeast and human cells (HeLa and U2OS). This suggests that the connections between metabolism and stress granule assembly might be broader than previously believed. Their focus on the product of Sam1, AdoMet, uncovered parallels between how metabolites regulate metabolism and stress granule formation/composition. Most provocatively, AdoMet administration to iPSC-derived motor neurones cells, suppressed stress granule formation that expressed mutated forms of TDP-43 and FUS found in ALS patients. AdoMet was effective in blocking stress granule assembly in these disease models.

Cells deploy a variety of mechanisms to fine-tune biochemical processes in response to environmental stressors. One of these mechanisms is the formation of stress granules. Stress granules assemble in response to a variety of nutrient and metabolic stresses and are believed to provide a mechanism for coupling metabolic stress to post-transcriptional gene regulation.

Furthermore, stress granules act as centers to regulate cell signaling outputs and protein folding, highlighting stress granules as global integrators of the stress response. stress granules are transient and require tight regulation of both assembly and disassembly for cell function and viability. For example, disruption of stress granule formation decreases cell survival when the stress is removed.

In addition to their role in integrating the cellular stress response, stress granules have been implicated in a variety of neurodegenerative disorders. Dysregulation in stress granule dynamics in ALS patients results in accumulation of atypical cytoplasmic, stress granule-like protein aggregates in dying neurons of the brain and spinal cord. These results argue that understanding how stress granules assemble in response to metabolic or nutrient stresses is critical for both understanding the pathophysiology of ALS and FTD and developing treatment strategies focused on disrupting the formation of aberrant stress granules.

Given the linkage between stress granules and several neurodegenerative diseases, the composition of the stress granule proteome has been a subject of intense focus to identify potential therapeutic targets. Unfortunately, large-scale biochemical studies have found that stress granule composition is not only stress specific, but also organism and cell type specific. Although different techniques have helped identify which components reside within each phase, the relative role of stress granule core proteins and shell proteins in stress granule formation and pathogenesis remains unclear.

Despite the fact that stress granule formation and composition is stress specific, there has been surprisingly little exploration of the connections between metabolism and stress granule assembly. To date, only a few metabolic enzymes have been shown to be enriched or localized to stress granules via proteomic and/or targeted studies. This deficit is likely due to the limited number of stress conditions that have been used in stress granule proteomic studies. Interestingly, the localization of one metabolic enzyme, pyruvate kinase (Cdc19), to stress granules has been shown to be crucial for reactivation of growth-promoting pathways upon removal of stress. This suggests that stress granules can play a critical role in regulating metabolic enzymes in response to stress.

There are also limited examples of the reverse mode of regulation: metabolic intermediates that modulate stress granule assembly. Whereas stress granules can assemble upon the removal of glucose or amino acids, only one metabolite from intermediate metabolism, acetyl-CoA, has been implicated in regulating stress granule formation. Thus, the identification of metabolic enzymes that are recruited to stress granules in a stress-specific manner would identify new linkages between stress granule formation and metabolism as well as provide a novel set of potential therapeutic targets for ALS and FTD.

In this article the researchers have identified 17 metabolic enzymes that are recruited to yeast stress granules in a stress-specific manner. S-adenosylmethionine (AdoMet), the product of one these enzymes, is a regulator of stress granule assembly and composition.

The regulation of yeast stress granule formation by AdoMet is biphasic, with chronic changes altering stress granule composition and acute elevation of AdoMet suppressing stress granule assembly. Additionally, acute elevation of AdoMet suppresses stress granule formation in motor neurones, demonstrating conserved metabolite regulation of stress granule assembly from yeast to humans. The suppressive effect of AdoMet on stress granule formation also occurs in induced pluripotent stem cell (iPSC)-derived motor neurones from ALS patients.

AdoMet blocks the recruitment of cytoplasmic TDP-43 to remnant stress granules in this cell culture, implying that AdoMet can modify the pathogenic accumulation of stress granule material. Together, these results argue that metabolic activity controls both the composition and extent of stress granule formation and provide a framework for the identification of lead compounds that can modify or suppress stress granule formation.

Recent work on the stress granule proteome suggests that stress granule composition can vary depending on the cell type and the nature of the stress. Because many of the stresses that trigger stress granule assembly are thought to alter metabolic activity, either directly or indirectly, one might expect metabolic enzymes to be a common component of stress granules. However, few metabolic enzymes have been identified in proteomic and targeted studies of Saccharomyces cerevisiae stress granules. Their identification of 17 metabolic enzymes that are recruited to stress granules in response to physiological nutrient stresses, but are not recruited to stress granules in response to multiple acute stresses, argues that stress granule composition is tailored to the nature of the stress and that chronic stresses might require reorganization of the metabolic network.

This result also helps to explain why no metabolic enzymes have been identified in previous proteomic studies of mammalian stress granules. All of the stresses that are traditionally used to induce mammalian stress granules, such as sodium azide, do not trigger the recruitment of metabolic enzymes to yeast stress granules. Thus, one might expect to observe metabolic enzymes only in stress granules that assemble in response to the mammalian equivalent of a stationary-phase nutrient stress.

As a final thought: Whose ALS patient, have not dream of a simple drug that would alleviate their symptoms? AdoMet is interesting to investigate.

Scientists from Korea and Germany, shown that human fibroblasts can be converted into induced motor neurons (iMNs) by sequentially inducing POU5F1(OCT4) and LHX3. This is a radical simplification in the process to induce fibroblasts in morphing into motor neurons. Fibroblasts are a common cell type found in conjonctive tissue. In addition the scientists transplanted those iMNs in a rodent spinal cord injury model. The iMNs promoted locomotor functional recovery.

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