Le sujet de l’alimentation des malades de la SLA ne fait guère l’objet d’études. Pourtant les malades de la SLA, tout au moins tant qu’ils ne sont pas alités de façon permanente, doivent recevoir plus d’énergie (de calories) qu’une personne en bonne santé. Il y a un calculateur en ligne sur ce site.

Tout d’abord il y a des problèmes méchaniques évidents, difficulté à avaler, mucus, risque de fausse route, problème de digestion, appétence. Trop souvent la diète se limite à ajouter un produit industriel enrichie en protéines.

Ensuite il y a le problème du choix des aliments et la confusion que le personnel médical (en dehors bien entendu des spécialistes de la SLA) peut faire entre les besoin des personnes en bonne santé et ceux des malades de la SLA. En effet dans la population générale, des taux accrus de triglycérides sont associés à une mortalité accrue en raison d'événements cardiovasculaires et il est souvent recommandé de réduire cet apport. Pourtant on sait que les personnes ayant un IMC d’environ 27 (surpoids) ont les meilleurs chances de survie.

Contrairement à ce qui est souvent affirmé, la perte de poids dans la SLA n’est pas seulement due à l’inactivité des moto-neurones (ce qui est le cas des accidentés ayant une section de la moelle épinière), mais aussi à la présence d’un important catabolisme. C’est à dire à un rythme de destruction des protéines qui est supérieur à celui de leur création.

Des effets bénéfiques ont été rapportés pour les interventions avec des suppléments nutritionnels riches en graisses, y compris une survie prolongée chez les patients à évolution rapide, une diminution de la fonction motrice, une stabilisation du poids corporel et une réduction des biomarqueurs. Voir cette étude, ou celle ci, ou encore celle là

Les triglycérides sont produits principalement par les hépatocytes et les adipocytes et sont largement issus des aliments. La fonction principale des triglycérides est de stocker et de transporter l'énergie sous forme d'acides gras dans les cellules et de fournir des sources d'énergie dans un état de pénurie de glucose via la conversion en glucose ou en corps cétoniques. Or les malades de la SLA sont souvent insulino-résistants donc leurs cellules sont en manque de glucose, c’est à dire d’énergie. Ainsi, des niveaux élevés de triglycérides pourraient potentiellement contrecarrer le catabolisme lié à la SLA.

À ce jour, le rôle des taux de lipides sanguins et leur association avec l'apparition et le pronostic de la SLA sont assez controversés. Voici une nouvelle recherche qui a exploré ces associations dans une vaste étude cas-témoin sur la population sdu ud-ouest de l'Allemagne. Cette nouvelle recherche confirme les résultats des études précédentes.

Entre 2010 et 2014, 336 patients SLA et 487 témoins appariés selon le sexe et l'âge de la même région géographique ont été recrutés dans le registre SLA du sud-ouest de l'Allemagne.

Les triglycérides et le cholestérol (lipoprotéines de haute densité (HDL), lipoprotéines de basse densité (LDL), total) ont été mesurés. Chez les patients SLA uniquement, des modèles de survie ont été utilisés pour évaluer la valeur pronostique.

Une concentration élevée de cholestérol total, a été trouvé associée au risque de SLA. Au contraire le risque de SLA n’a pas été associé aux taux de HDL, de LDL ou de triglycérides, ni au rapport LDL-HDL. En revanche, des taux de triglycérides plus élevés étaient associés à une mortalité plus faible.

Ces résultats soulignent l'importance de distinguer l’impact du cholestérol de celui des triglycérides lorsque l'on considère le rôle pronostique du métabolisme des lipides dans la SLA.

Cela renforce encore la justification d'un régime riche en triglycérides dans le cadre de la SLA, tandis que l'impact négatif du cholestérol doit être exploré plus avant.

La dérégulation du fer a été impliquée dans de multiples maladies neurodégénératives, y compris la maladie de Parkinson et la sclérose latérale amyotrophique (SLA). Les cellules constituant la microglie se trouvent fréquemment chargées de fer dans les régions cérébrales touchées, mais la façon dont l'accumulation de fer influence la physiologie de la microglie et contribue à la neurodégénérescence est mal comprise.

Dans une nouvelle publication, les auteurs montrent qu'une tri-culture de cellules de microglie dérivée de cellules souches pluripotentes humaines est très sensible au fer et sensible à la ferroptose, une forme de mort cellulaire dépendante du fer. La microglie est une population de cellules gliales — des macrophages que l'on retrouve dans le système nerveux central et qui en forme la principale défense immunitaire active grâce à ses capacités phagocytaires. Les cellules gliales sont les cellules qui forment l'environnement des neurones. Elles jouent un rôle de soutien et de protection du tissu nerveux en apportant les nutriments et l'oxygène, en éliminant les cellules mortes et en combattant les pathogènes.

Les cultures in vitro d'astrocytes et de microglies sont des outils puissants pour étudier les voies moléculaires spécifiques impliquées dans la neuroinflammation. Cependant, afin de mieux comprendre l'influence de la diaphonie cellulaire sur la neuroinflammation, de nouveaux modèles de culture multicellulaires sont nécessaires. En effet, les interactions entre les neurones, les astrocytes et la microglie influencent de manière critique les réponses neuro-inflammatoires à l'insulte dans le système nerveux central. La « tri-culture » composée à la fois de neurones, d'astrocytes et de microglie imite plus fidèlement les réponses neuro-inflammatoires in vivo que les mono-cultures standard.

Parmi les trois types de cellules, la microglie a eu la réponse transcriptionnelle la plus forte à la dérégulation du fer, et les scientifiques ont identifié un sous-ensemble de microglie avec une signature transcriptomique distincte associée à la ferroptose qui est enrichie dans la moelle épinière SLA post-mortem et la microglie du mésencéphale du patient PD post-mortem.

L'élimination de la microglie du système de tri-culture a considérablement retardé la neurotoxicité induite par le fer.

Dans la maladie, l'absorption microgliale de fer peut initialement être protectrice, mais, lorsque les cellules succombent à la ferroptose, elles entrent dans un état cellulaire neurotoxique qui entraîne des lésions et elles meurent en masse.

Pour élucider les mécanismes régulant la réponse du fer dans la microglie, les scientifiques ont effectué un criblage CRISPR à l'échelle du génome et identifié de nouveaux régulateurs de la ferroptose, y compris le gène de trafic de vésicule SEC24B. Enfin, les auteurs ont effectué un criblage de petites molécules pour identifier les inhibiteurs de la ferroptose de la microglie. Sur les 546 composés, ils ont trouvé 39 composés qui inhibaient la ferroptose dans la microglie. Parmi ceux-ci Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP ou encore sésamol. La rhapontigénine est un stilbénoïde. Il peut être isolé de la vigne du Japon (Vitis coignetiae) ou du Gnetum cleistostachyum. Il montre une action sur les cellules cancéreuses de la prostate. Il a été démontré qu'il inhibe le cytochrome humain P450 1A1, une enzyme impliquée dans la biotransformation d'un certain nombre de composés cancérigènes et immunotoxiques. Le xanthotoxol est une furanocoumarine. C'est l'un des principes actifs majeurs de Cnidium monnieri. Cnidium monnieri (L.) Cuss. est l'une des plantes médicinales traditionnelles les plus largement utilisées et ses fruits ont été utilisés pour traiter diverses maladies en Chine, au Vietnam et au Japon. Le sésamol est un composé organique naturel qui entre dans la composition des graines de sésame et de l'huile de sésame, aux propriétés anti-inflammatoires, antioxydantes, antidépressives et neuroprotectrices.

Malgré le fait que la ferroptose a été impliquée dans de nombreux troubles, on ne connait aucun traitement efficace pour atténuer la ferroptose. Les chélateurs du fer sont une approche potentielle, mais beaucoup od'entre eux peuvent perturber les fonctions redox homéostatiques. Cependant, les études précliniques existantes utilisant des inhibiteurs de la peroxydation lipidique, tels que lip-1, et les données présentées dans cette étude fournissent une justification solide pour le développement de thérapies ciblant la ferroptose. Plusieurs composés ciblant la peroxydation lipidique et le stress oxydatif sont d'ailleurs en cours d'essais cliniques, notamment le dérivé de la vitamine E vatiquinone, l'acide linoléique deutéré et les activateurs de la voie antioxydante NRF2.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Cells making up microglia are frequently found loaded with iron in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood.

In a new publication, authors show that a tri-culture of microglia cells derived from human pluripotent stem cells is highly iron-sensitive and susceptible to ferroptosis, a form of iron-dependent cell death.

Microglia is a population of glial cells, macrophages that are found in the central nervous system and which form the main active immune defense thanks to their phagocytic abilities. Glial cells are the cells that form the environment of neurons. They play a role in supporting and protecting nervous tissue by providing nutrients and oxygen, eliminating dead cells and fighting pathogens.

In vitro cultures of astrocytes and microglia are powerful tools to study the specific molecular pathways involved in neuroinflammation. However, in order to better understand the influence of cell crosstalk on neuroinflammation, new multicellular culture models are needed. Indeed, interactions between neurons, astrocytes and microglia critically influence neuroinflammatory responses to insult in the central nervous system. The "tri-culture" composed of both neurons, astrocytes and microglia more closely mimics neuro-inflammatory responses in vivo than standard mono-cultures.

Of the three cell types, microglia had the strongest transcriptional response to iron dysregulation, and scientists identified a subset of microglia with a distinct transcriptomic signature associated with ferroptosis that is enriched in the spinal cord Postmortem ALS and midbrain microglia from postmortem PD patient.

Removal of microglia from the tri-culture system significantly delayed iron-induced neurotoxicity.

In the disease, microglial iron uptake may initially be protective, but when cells succumb to ferroptosis, they enter a neurotoxic cellular state that leads to damage and they die en masse.

To elucidate the mechanisms regulating the iron response in microglia, scientists performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. Finally, the authors performed a small molecule screen to identify inhibitors of microglia ferroptosis. Of the 546 compounds, they found 39 compounds that inhibited ferroptosis in microglia. Among these Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP or sesamol.

Rhapontigenin is a stilbenoid. It can be isolated from Japanese grapevine (Vitis coignetiae) or Gnetum cleistostachyum. It shows an action on prostate cancer cells. It has been shown to inhibit human cytochrome P450 1A1, an enzyme involved in the biotransformation of a number of carcinogenic and immunotoxic compounds. Xanthotoxol is a furanocoumarin. It is one of the major active principles of Cnidium monnieri. Cnidium monnieri (L.) Cuss. is one of the most widely used traditional herbal medicines and its fruits have been used to treat various diseases in China, Vietnam and Japan. Sesamol is a natural organic compound that is part of the composition of sesame seeds and sesame oil, with anti-inflammatory, antioxidant, antidepressant and neuroprotective properties.

Despite the fact that ferroptosis has been implicated in many disorders, no effective treatment is known to alleviate ferroptosis. Iron chelators are a potential approach, but many of them can disrupt homeostatic redox functions. However, the existing preclinical studies using lipid peroxidation inhibitors, such as lip-1, and the data presented in this study provide strong rationale for the development of therapies targeting ferroptosis. Several compounds targeting lipid peroxidation and oxidative stress are also in clinical trials, including the vitamin E derivative vatiquinone, deuterated linoleic acid and activators of the antioxidant pathway NRF2.

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I am not sure of the value of this study, yet as it is well known that a bile acid (TUDCA) may have benefits in ALS, so every story making a connection between bile acids and ALS may be of interest.

Recent studies suggest that the bile acid metabolism is associated with cognitive function.

Cognitive impairments and behavioral abnormalities in 35% of patients with amyotrophic lateral sclerosis (ALS) have been reported. However, the underlying mechanisms have been poorly understood. Mutations in the C9orf72 gene explain the association between ALS and frontotemporal dementia. About 5%–15% of Western ALS patients satisfy the diagnostic criteria for frontotemporal dementia. An intriguing fact is that this C9orf72 mutation barely occurs in Chinese ALS patients, yet about 40% of Chinese ALS patients exhibited CI and that 30% had behavioral abnormalities.

In the current study, the authors explored the role of gut microbiota in cognitive impairment of ALS patients. They collected fecal samples from 35 ALS patients and 35 healthy controls. The scientists analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted (bile acids) metabolite mapping between patients with cognitive impairment and patients with normal cognition.

They found altered gut microbial communities and a lower ratio of Firmicutes/ Bacteroidetes in the cognitive impairment group, compared with the normal cognition group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the cognitive impairment group, compared with the normal cognition group.

These metabolites were mapped to the metabolic pathways associated with bile acids. They further found that cholic acid and chenodeoxycholic acid were significantly lower in the cognitive impairment group than in the normal cognition group. Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans.

As primary bile acids move from the small intestine to the colon, they are converted to secondary bile acides (including TUDCA) by the biotransformation of the resident microbial community. So bile acids changes may be associated with a microbiome change in ALS patients.

Bile acids are essential products of cholesterol metabolism. Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. Similarly a defect in lipid (cholesterol) metabolism may induce cognitive changes. But this is still highly hypothetical.

In conclusion, the authors found that the gut microbiota and its metabolome profile differed between ALS patients with and without cognitive impairment and that the altered bile acid profile in fecal samples was significantly associated with cognitive impairment in ALS patients.

These results need to be replicated in larger studies in the future.

This article is a bit unusual as it claims a relationship between several genes in ALS (Lou Gerigh disease), including APP which is associated with Alzheimer's disease. On the overall it says that C9 ALS is a problem of ribosome quality control (RQC) which leads to cellular stress response. It suggests that C9, FUS, TDP-43 mutations influence mTORC2 protein which in turn alters the translation mechanism. When the translation mechanism is altered, cellular stress response is activated and protein production nearly stops, rendering the cell non-functional. It's the start of the disease.

ALS is a muscle wasting disease characterized by degeneration of lower motor neurons and axons and loss of upper motor neurons and their corticospinal tracts. FTD is a progressive neuronal atrophy with neuronal loss in the frontal and temporal cortices and associated behavioral and personality changes and impairment of language skills. Advances in human genetics have identified multiple genetic mutations commonly associated with ALS and FTD, revealing that these two diseases are related and may represent a continuum of a broad neurodegenerative disorder. C9orf72 mutation is present in approximately 40% of familial ALS and 8-10 % of sporadic ALS. It is currently the most common demonstrated mutation related to ALS - far more common than SOD1.

The research on association of C9ORF72 with ALS or FTD is relatively recent and its mechanisms are not clear. This obviously impairs the proposal of new drugs. Gene expression or translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription of DNA to RNA in the cell's nucleus. Yet during translation elongation, ribosomes may slowdown or even stall for various reasons. The polypeptide later folds into an active protein and is sent to its final location to perform its functions in the cell.

RAN translation, is an irregular mode of mRNA translation that can occur in eukaryotic cells. RAN translation produces a variety of dipeptide repeat proteins (DPR) by translation of expanded hexanucleotide repeats present in an intron of the C9orf72 gene. The expansion of the hexanucleotide repeats and thus accumulation of dipeptide repeat proteins are thought to cause cellular toxicity that leads to neurodegeneration in ALS disease.

Previous studies of protein quality control have focused on how proteins were handled after translation. However, rproblems with proteostasis are prevalent even with translating nascent peptide chains still associated with ribosomes, necessitating ribosome-associated quality control (RQC) mechanisms.

Mutations in other genes that are commonly linked to ALS/FTD have also shed lights on disease pathogenesis such as TDP-43 and FUS. Other genes linked to ALS/FTD include VCP, a member of the AAA ATPase family with established function in the recycling and degradation of ubiquitinated proteins, and genes with functions in protein clearance or maintenance of protein homeostasis. In addition, upregulation of APP, a protein whose aberrant processing or metabolism having been implicated in Alzheimer’s disease (AD), was observed at early stages of ALS and FTD, presumably as a compensatory response to neuronal damage or impairment of axonal transport. However, the relationships among the various ALS/FTD genes remain underexplored.

It is therefore important to understand cellular mechanisms underlying the quality control of poly(GR). Previous studies of protein quality control have focused on how proteins were handled after translation, e.g., by chaperone-mediated refolding, or proteasome- and lysosome-mediated degradation. However, recent studies reveal that problems with proteostasis are prevalent even with translating nascent peptide chains still associated with ribosomes, necessitating ribosome-associated quality control (RQC) mechanisms.

In the case of poly(GR), it was shown that its translation was frequently stalled, presumably due to positively charged arginine residues interacting with negatively-charged residues lining the exit tunnel of 60S ribosome. Stalled poly(GR) translation activates the RQC process, the inadequacy of which can lead to the accumulation of aberrant, C-terminally modified (CAT-tailed) poly(GR) species that can perturb proteostasis and contribute to poly(GR) accumulation and neuromuscular degeneration.

In this study, the scientists from USA and China set out to test whether the other ALS/FTD associated genes may participate in the quality control of poly(GR). Strikingly, they discovered that overexpression of APP, FUS, and TDP-43 restrains poly(GR) protein expression. Mechanistically, APP, FUS and TDP-43 act through the mTORC2/AKT/VCP axis to regulate the RQC of poly(GR) translation. Inhibition of the mTORC2/AKT/VCP axis could restore poly(GR) protein expression attenuated by APP, FUS, or TDP-43. Their data strongly implicate the mTORC2/AKT/VCP axis as a major regulator of protein quality control in ALS/FTD.

Their data support the working model that mutated APP, FUS, and TDP-43 are upstream regulators of the mTORC2/AKT/VCP axis, which regulates the RQC of poly(GR) during its translation stalling. Moreover, they suggest that APP, FUS, and TDP-43 can also induce repression of global translation when ribosome stalling is persistent.

APP acts through the mTORC2/AKT signaling axis to regulate the RQC of C9-ALS/FTD-associated poly(GR) translation. The involvement of APP in ALS has previously been studied in the context of ALS, and APP or its metabolite was found to exacerbate ALS-related phenotypes in the SOD1-G93A mouse model. This new results suggest that APP can activate mTORC2/AKT signaling to alleviate stalled translation of poly(GR) and restrain the expression of aberrant poly(GR) translation products, at least at the initial stage. It is possible that in ALS/FTD setting, APP is upregulated as a protective response in response to neuronal damage at an early stage of disease as previously suggested

It is difficult to not think about the controverse about the role of amyloid plaques found in the brains of Alzheimer's disease patients. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair. While the authors write only about ALS, chronic upregulation of APP may contribute not only to ALS, but also also to Alzheimer's disease due to the accumulation of APP metabolites, the stalled translation of APP itself, or the prolonged activation of stress response pathways by APP may lead to the depression of global translation.

Indeed the authors found that integrated stress response as indicated by eIF2α phosphorylation was heightened in transgenic flies expressing poly(GR). This is presumably caused by the ribosome stalling occurring during poly(GR) translation.

A similar situation may occur with TDP-43 and FUS. In fact, both mutations in TDP-43 and FUS genes have been shown to associate with stalled ribosomes, and in the case of TDP-43, its association with stalled ribosomes provides neuroprotection function in the face of sublethal stress.

Intriguingly, the authors showed that the a portion of APP (APP-C99) is sufficient to activate the mTORC2/AKT axis and regulate GR80 translation, whereas the Aβ-42 portion of APP was without effect. This finding resonates with recent revelation of aberrant APP-C99 as the etiological driver of Alzheimer’s disease.

Remarkably, the translation of this portion of APP is also frequently stalled, the inadequate RQC of which can generate aberrant translation products that precipitate hallmarks of Alzheimer’s disease. It is therefore fascinating that overexpression one stalled translation product (APP-C99) would abrogate the stalled translation of another portion (GR-80).

Future studies will investigate at the biochemical level how APP/APP-C99, FUS, and TDP-43 signal to the mTORC2/AKT/VCP axis to regulate the RQC of stalled poly(GR) translation, whether endogenous stalled peptides that serve as RQC substrate(s) may also targeted by this pathway, and how this signaling process may be targeted for therapeutic purposes.

La consommation d'un régime riche en graisses provoque diverses maladies métaboliques, notamment le syndrome métabolique et le diabète de type 2 en développant une résistance à l'insuline et même en diminuant la production d'insuline.

Par exemple un bon moyen d'induire un syndrome de Parkinson chez les rats est de leur donner un régime alimentaire très riche en graisse. On a parfois qualifié la maladie d'Alzheimer comme étant diabète de type 3.

Un mystère est celui de la SLA (maladie de Charcot) où on a souvent une résistance à l'insuline, mais très rarement un diabète en comorbidité. Il semble aussi que l'existence protéines mal repliées dans le cytoplasme des malades soit liée à un stress du réticulum endoplasmique, un organe des cellules dont la fonction est justement de replier les protéines nouvellement produites par les ribosomes, avant leur expédition vers leur destination dans l'appareil de Golgi.

Une exposition à long terme aux acides gras saturés (acides gras saturés) dans les cellules β pancréatiques provoque une désensibilisation et une altération de la sécrétion d'insuline.

Par exemple, la consommation pendant trois mois de régime alimentaire très riche en graisse contenant de la graisse de porc et de l'huile de tournesol (80 % de graisse) réduit chez la souris la teneur en insuline des îlots pancréatiques (50 %), l'ARNm de la proinsuline (35 %), la biosynthèse et la sécrétion de l'insuline en réponse au glucose (50 %) , et l'oxydation du glucose.

Selon des recherches antérieures, WFS1 (syndrome de Wolfram 1) est impliqué dans la synthèse et la libération d'insuline, ainsi que dans la préservation de la masse des cellules β pancréatiques. Ce gène Wfs1 a été identifié pour la première fois par Wolfram et Wagener (1983) chez des patients atteints du syndrome de Wolfram (c.-à-dire un diabète sucré et une atrophie du nerf optique).

Le gène WFS1 exprime une glycoprotéine dans le réticulum endoplasmique (réticulum endoplasmique) des cellules β pancréatiques, du cœur, du placenta, des poumons et du cerveau.

Les acides gras saturés comme le palmitate induisent un stress réticulum endoplasmique. Des études ont montré qu'il existe une relation mutuelle entre le stress oxydatif et le stress réticulum endoplasmique. On l'acide trouve dans l'huile de palme, mais aussi dans toutes les graisses et huiles animales (beurre, fromage, lait et viande) ou végétales.

Pendant le stress du réticulum endoplasmique, l'expression de WFS1 augmente pour inhiber la signalisation de ce stress et ainsi empêcher l'apoptose (l'un des processus aboutissant à la mort de la cellule).

Etant donné le rôle de la protéine WFS1 dans le maintien de l'homéostasie du réticulum endoplasmique, on s'attend à ce que l'expression de cette protéine soit augmentée dans le réticulum endoplasmique des cellules β, et sa translocation vers le cytoplasme est réduite et conduit à une diminution du GSIS des îlots pancréatiques et teneur en insuline.

Bien que de nombreuses études aient étudié les effets de chaque régime alimentaire très riche en graisse et l'implication de WFS1 dans la synthèse et la sécrétion d'insuline, aucune étude n'a examiné l'interaction de régime alimentaire très riche en graisse et WFS1 en relation avec la synthèse et la sécrétion d'insuline et donc l'homéostasie du glucose.

Après le sevrage, les rats ont été divisés en six groupes et nourris avec un régime alimentaire normal et régime alimentaire très riche en graisse (30%) pendant 20 semaines, puis de l'acide 4-phényl butyrique (4-PBA, un inhibiteur du stress réticulum endoplasmique) a été administré. On notera qu'il s'agit d'une des deux composantes de l'AMX0035.

Après avoir effectué un test de tolérance au glucose, les animaux ont été disséqués et leurs pancréas ont été prélevés pour extraire l'réticulum endoplasmique, l'isolement des îlots et l'évaluation du GSIS. De plus, les biomarqueurs du stress du réticulum endoplasmique pancréatique.

Ce régime alimentaire très riche en graisse a diminué les niveaux de protéine pancréatique WFS1 et de GSH, et augmenté l'activité de la catalase pancréatique. En conséquence, il a augmenté les niveaux de protéines BIP, CHOP et WFS1 dans le RE extrait du pancréas. De plus, le régime alimentaire très riche en graisse a provoqué une intolérance au glucose et a diminué la teneur en GSIS et en insuline des îlots.

Cependant, l'administration de 4-PBA a restauré les niveaux antérieurs. Il semble donc bien que la consommation de régime alimentaire très riche en graisse en induisant un stress réticulum endoplasmique pancréatique ait altéré les niveaux d'expression de WFS1, réduit la teneur en GSIS et en insuline des îlots et finalement altéré l'homéostasie du glucose.

L'administration de 4-PBA ne me semble pas être une solution au problème du stress du réticulum endoplasmique, par contre c'est certainement un moyen de pallier à une conséquence dramatique de ce stress: La mort cellulaire, ce qui dans le cas de la SLA intervient très certainement sur les cellules qui consomment le plus d'énergie comme les muscles squelettiques et les neurones moteurs.

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If you have ever wondered how drugs are selected for clinical trials and assumed, as often described, that they must be selected after lengthy preclinical studies in animal models, here is an article that will disappoint you.

50 scientists in Scotland conducted a two-stage systematic review to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870).

Obviously this could only lead to drugs that were already tested either in preclinical studies or in drugs trials.

Indeed the repurposing of drugs reduces costs and barriers to clinical development because they have been assumed by someone else, this is for example the strategy used by Amylyx for AMX0035.

First, the authors reviewed clinical studies in Motor neuron disease, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one Motor neuron disease publication or publications in two or more other diseases.

The authors scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, the authors reviewed efficacy of drugs in Motor neuron disease animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies.

An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in Motor neuron disease-SMART.

Curiously those experts eliminated Sodium phenylbutyrate which is one component of AMX0035.

We learn also they rightly eliminated drugs that were already trialed four times or more. As the saying tells: "Errare humanum est, perseverare autem diabolicum."

The seven candidate drugs remaining were memantine, acetyl-l-carnitine, simvastatin, ciclosporin, melatonin, fluoxetine and N-acetyl cysteine.

For future drug selection, the authors will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

This statement is in itself a bit bizarre, there are many AI tools for discovering drugs, some are open source, some are commercial, but in most cases they are of good to excellent quality. Drug selection with a literature review sounds like a process from the dark ages.

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Consuming a high fat diet causes various metabolic diseases including metabolic syndrome and type 2 diabetes by developing insulin resistance and even decreasing insulin production.

For example a good way to induce Parkinson's syndrome in rats is to feed them a very high fat diet. Alzheimer's disease has sometimes been referred to as type 3 diabetes.

A mystery is that of ALS (Charcot's disease) where we often have insulin resistance, but very rarely comorbid diabetes. It also seems that the existence of misfolded proteins in the cytoplasm of patients is linked to stress in the endoplasmic reticulum, a cell organ whose function is precisely to fold the proteins newly produced by the ribosomes, before they are sent to their destination in the Golgi apparatus.

Long-term exposure to saturated fatty acids (SAFAs) in pancreatic β cells causes desensitization and impaired insulin secretion.

For example, consumption for three months of a very high fat diet containing pork fat and sunflower oil (80% fat) reduced the insulin content of pancreatic islets in mice (50%), proinsulin mRNA (35%), insulin biosynthesis and secretion in response to glucose (50%), and glucose oxidation.

According to previous research, WFS1 (Wolfram syndrome 1) is involved in insulin synthesis and release, as well as mass preservation of pancreatic β cells. This Wfs1 gene was first identified by Wolfram and Wagener (1983) in patients with Wolfram syndrome (i.e. diabetes mellitus and optic nerve atrophy).

The WFS1 gene expresses a glycoprotein in the endoplasmic reticulum (endoplasmic reticulum) of pancreatic β cells, heart, placenta, lungs and brain.

Saturated fatty acids like palmitate induce endoplasmic reticulum stress. Studies have shown that there is a mutual relationship between oxidative stress and endoplasmic reticulum stress. It is found in palm oil, but also in all animal (butter, cheese, milk and meat) or vegetable fats and oils.

During endoplasmic reticulum stress, WFS1 expression increases to inhibit stress signaling and thus prevent apoptosis (one of the processes leading to cell death).

Given the role of the WFS1 protein in maintaining endoplasmic reticulum homeostasis, it is expected that the expression of this protein is increased in the endoplasmic reticulum of β-cells, and its translocation to the cytoplasm is reduced. and leads to a decrease in pancreatic islet GSIS and insulin content.

Although many studies have investigated the effects of each very high fat diet and the involvement of WFS1 in insulin synthesis and secretion, no study has examined the interaction of very high fat diet and WFS1 in relation to insulin synthesis and secretion and therefore glucose homeostasis.

After weaning, the rats were divided into six groups and fed a normal diet and a very high fat (30%) diet for 20 weeks, followed by 4-phenyl butyric acid (4-PBA, an inhibitor endoplasmic reticulum stress) was administered. Note that this is one of the two components of the AMX0035.

After performing a glucose tolerance test, the animals were dissected and their pancreases removed for endoplasmic reticulum extraction, islet isolation, and GSIS evaluation. Additionally, pancreatic endoplasmic reticulum stress biomarkers.

This very high-fat diet decreased pancreatic protein WFS1 and GSH levels, and increased pancreatic catalase activity. As a result, it increased the levels of BIP, CHOP and WFS1 proteins in the ER extracted from the pancreas. In addition, the very high-fat diet caused glucose intolerance and decreased GSIS and insulin content of islets.

However, administration of 4-PBA restored previous levels. It therefore appears that consumption of very high fat diet by inducing pancreatic endoplasmic reticulum stress altered WFS1 expression levels, reduced GSIS and islet insulin content and ultimately impaired glucose homeostasis.

The administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which

Yet, administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which in the case of ALS most certainly affects the cells that consume the most energy, such as skeletal muscles and motor neurons.

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