The formation of stress granules, which are large assemblies composed mainly of proteins and mRNA, have been reported under various stress conditions, such as starvation, osmotic, thermal and oxidative stresses, and are believed to be one of the means that cells use to adapt to cellular stress.

In addition, many neurodegenerative diseases are characterized by protein aggregates very similar to stress granules. This is the case for example for Alzheimer's disease but also for Parkinson's disease, Amyotrophic Lateral Sclerosis and others.

Indeed stress granules protect the cell from environmental stress, but under prolonged stress, they turn into abnormal aggregates, but the underlying molecular mechanism of the self-assembly process is poorly understood.

Cell starvation stress is common in cases of ALS, it can be found in situations like mutations (eg C9orf73) which require special efforts from the cellular protein quality system or when faced with insulin resistance which reduces the cellular supply of glucose. Acidification of the cellular extracellular medium (low pH) and concomitant intracellular alkalinization of the cytoplasm (high pH) are characteristics of cancer.

In this study, the authors show that under low pH conditions, imitating starvation cellular stress, the central part of TDP-43 which includes the two RRM motifs (TDP-43tRRM), undergoes a conformational change linked to the protonation of buried ionizable residues and develops into a metastable oligomeric assembly called low pH form '' or the L form ''.

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The authors have thus shown that in the presence of acidification, even very weak, TDP-43tRRM folds completely and oligomerizes to form a "β form" rich in β sheets. The β form has an ordered and stable structure that resembles the amyloid fibrils that are found in Alzheimer's disease!


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.

La formation de granules de stress, qui sont de grands assemblages composés principalement de protéines et d'ARNm, ont été signalés dans diverses conditions de stress, telles que la famine, les stress osmotiques, thermiques et oxydatifs, et on pense qu’ils sont l’un des moyens que les cellules utilisent pour s’adapter au stress cellulaire.

Par ailleurs de nombreuses maladies neurodégénératives sont caractérisées par des agrégats de protéines ressemblant beaucoup aux granules de stress. C’est le cas par exemple pour la maladie d’Alzheimer mais aussi pour la maladie de Parkinson, la Sclérose Latérale Amyotrophique et d’autres.

Les granules de stress protègent la cellule du stress environnemental, mais sous un stress prolongé, ils se transforment en agrégats anormaux. Il est connu que des facteurs sporadiques, sont responsables de cette agrégation dans la majorité (90-95%) des cas de SLA, mais le mécanisme moléculaire sous-jacent du processus d'auto-assemblage est mal compris.

Le stress cellulaire de famine est courant dans les cas de SLA, on peut le trouver dans des situations comme les mutations (par exemple C9orf73) qui nécessitent des efforts particuliers du système de qualité de production de protéine ou face à une résistance à l’insuline qui réduit l’approvisionnement cellulaire en glucose. Le stress cellulaire chronique provoque également le cancer. L'acidification du milieu extracellulaire cellulaire (pH bas) et l'alcalinisation intracellulaire concomitante du cytoplasme (pH élevé) sont des caractéristiques du cancer.

Dans cette étude, les auteurs montrent que dans des conditions de faible pH, imitant le stress cellulaire de famine, la partie centrale de TDP-43 qui comprend les deux motifs RRM (TDP-43tRRM) subit une réaction d'ouverture conformationnelle liée à la protonation des résidus ionisables enfouis et se développe en un assemblage oligomère métastable appelé forme à faible pH '' ou le forme en L'. enter image description here Les auteurs ont montré qu'en présence d’une acidification, même très faible, le TDP-43tRRM se replie complètement et s'oligomérise pour former une «forme β» riche en feuillets β. La forme β a une structure ordonnée et stable qui ressemble aux fibrilles amyloïdes que l'on trouve dans la maladie d'Alzheimer!


Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

ALS has been linked by many scientists to an abnormal lipid metabolism and, in particular, to gangliosides and their ceramide-type precursors which are thought to be modulators of the progression of the disease. Interestingly, autoantibodies against specific gangliosides produce an inflammatory disease of the spinal motor neurons which is known as conduction multifocal motor neuropathy (Harschnitz et al., 2014).

Overall, there is substantial evidence of ganglioside dysfunction in neurodegenerative diseases, for example for ALS, Alzheimer's disease, Huntington's disease and Parkinson's disease.

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The exact nature of the problems, however, appears to be variable in these different diseases; for example ganglioside concentrations are reduced in Parkinson's disease and Huntington's disease, but increased in Alzheimer's disease and there are two-way changes for ALS.

Glycan and polysaccharide are synonymous, however, in practice, the term glycan can also be used to refer to a glycoprotein, a glycolipid or a proteoglycan. Glycolipids are lipids with a carbohydrate linked by a glycosidic bond (covalent). Their role is to maintain the stability of the cell membrane and facilitate cell recognition, which is crucial for the immune response and in the connections that allow cells to connect to each other to form tissue.

Sphingolipidoses are a class of lipid storage disorders linked to the metabolism of sphingolipids (a glycolipid). Sphingolipids were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play an important role in signal transduction and cell recognition. Sphingolipidosis, or disorders of sphingolipid metabolism, have a particular impact on neural tissue. The main diseases of these disorders are Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease and metachromatic leukodystrophy.

There are simple sphingolipids, which include sphingoid bases and ceramides as well as complex sphingolipids.

Sceramides have been implicated in various medical conditions, including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity and inflammation. Ceramides induce insulin resistance in skeletal muscles, as well as induction of insulin resistance in many tissues. In the mitochondria, ceramide suppresses the electron transport chain and induces the production of reactive oxygen species.

Complex sphingolipids include Sphingomyelin which is found in the membranes of animal cells, particularly in the membranous myelin sheath which surrounds certain axons of nerve cells. They also include glycosphingolipids which can themselves be divided into cerebrosides, gangliosides and globosides.

Gangliosides have been shown to be very important molecules in immunology. Natural and semi-synthetic gangliosides are considered as possible therapies for neurodegenerative disorders. Gangliosides are present and concentrated on cell surfaces, where they present points of recognition for extracellular molecules or the surfaces of neighboring cells. They are mainly found in the nervous system.

A number of studies have implicated glycosyltransferases in the pathogenesis of neurodegenerative diseases, but it has been difficult to differentiate the cause of the effect. Scientists recently discovered [0] that mutations near the substrate binding site of the glycosyltransferase 8 domain containing 1 (GLT8D1) are associated with familial amyotrophic lateral sclerosis (ALS). The study authors demonstrated that mutations associated with ALS reduce the activity of the enzyme, suggesting a mechanism of loss of function that is an attractive therapeutic target. Their work shows that an isolated dysfunction of a glycosyltransferase is enough to cause degenerative diseases.

Several glycan-based therapies have been developed. In particular, glycosylation modulators that affect glycan uptake can be powerful tools for developing glycan-based therapies.

[0] Disrupted glycosylation of lipids and proteins isa cause of neurodegeneration. Tobias Moll, Pamela J. Shaw and Johnathan Cooper-Knock doi:10.1093/brain/awz358


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.

La SLA a été liée par de nombreux scientifiques à un métabolisme lipidique anormal et, en particulier, aux gangliosides et leurs précurseurs de type céramide qui seraient des modulateurs de la progression de la maladie. Fait intéressant, les auto-anticorps contre des gangliosides spécifiques produisent une maladie inflammatoire des motoneurones spinaux qui est connue sous le nom de neuropathie motrice multifocale avec conduction (Harschnitz et al., 2014).

Dans l’ensemble, il existe des preuves substantielles de dysfonctionnement des gangliosides dans les maladies neurodégénératives, par exemple pour la SLA, la maladie d’Alzheimer, la maladie de Huntington et la maladie de Parkinson. enter image description here La nature exacte des problèmes apparaît cependant être variable dans ces différentes maladies; par exemple les concentrations de ganglioside sont réduites dans la maladie de Parkinson et la maladie de Huntington, mais augmentées dans la maladie d’Alzheimer et y a des altérations dans les deux directions pour la SLA.

Glycane et polysaccharide sont synonymes, cependant, dans la pratique, le terme glycane peut également être utilisé pour désigner une glycoprotéine, un glycolipide ou un protéoglycane. Les glycolipides sont des lipides avec un glucide lié par une liaison glycosidique (covalente). Leur rôle est de maintenir la stabilité de la membrane cellulaire et de faciliter la reconnaissance cellulaire, qui est cruciale pour la réponse immunitaire et dans les connexions qui permettent aux cellules de se connecter les unes aux autres pour former des tissus.

Les sphingolipidoses sont une classe de troubles du stockage des lipides liés au métabolisme des sphingolipides (un glycolipide). Les sphingolipides ont été découverts dans des extraits de cerveau dans les années 1870 et ont ainsi été nommés d’après le sphinx mythologique à cause de leur nature énigmatique. Ces composés jouent un rôle important dans la transduction du signal et la reconnaissance cellulaire. Les sphingolipidoses, ou troubles du métabolisme des sphingolipides, ont un impact particulier sur le tissu neural. Les principales maladies de ces troubles sont la maladie de Niemann-Pick, la maladie de Fabry, la maladie de Krabbe, la maladie de Gaucher, la maladie de Tay-Sachs et la leucodystrophie métachromatique.

Il existe des sphingolipides simples, qui comprennent les bases sphingoïdes et les céramides ainsi que les sphingolipides complexes.

Le scéramides ont été impliqués dans divers états pathologiques, notamment le cancer, la neurodégénérescence, le diabète, la pathogenèse microbienne, l’obésité et l’inflammation. Les céramides induisent une résistance à l’insuline des muscles squelettiques, ainsi qu’une induction de la résistance à l’insuline dans de nombreux tissus. Dans les mitochondries, le céramide supprime la chaîne de transport d’électrons et induit la production d’espèces réactives de l’oxygène.

Les sphingolipides complexes incluent la Sphingomyéline qui se trouve dans les membranes des cellules animales, en particulier dans la gaine de myéline membraneuse qui entoure certains axones des cellules nerveuses. Ils comprennent également les glycosphingolipides qui peuvent eux-même être divisés en cérébrosides, gangliosides et globosides.

Les gangliosides se sont révélés être des molécules très importantes en immunologie. Les gangliosides naturels et semi-synthétiques sont considérés comme des thérapies possibles pour les troubles neurodégénératifs. Les gangliosides sont présents et concentrés sur les surfaces cellulaires, où ils présentent des points de reconnaissance pour les molécules extracellulaires ou les surfaces des cellules voisines. Ils se trouvent principalement dans le système nerveux.

 Un certain nombre d’études ont impliqué des glycosyltransférases dans la pathogenèse des maladies neurodégénératives, mais il a été difficile de différencier la cause de l’effet. Des scientifiques ont récemment découvert [0] que des mutations à proximité du site de liaison du substrat du domaine de la glycosyltransférase 8 contenant 1 (GLT8D1) sont associées à la sclérose latérale amyotrophique familiale (SLA). Les auteurs de l’étude ont démontré que les mutations associées à la SLA réduisent l’activité de l’enzyme, suggérant un mécanisme de perte de fonction qui est une cible thérapeutique attrayante. Leur travail est montre qu’un dysfonctionnement isolé d’une glycosyltransférase est suffisant pour provoquer des maladies dégénératives.

Plusieurs thérapies à base de glycane ont été développées. En particulier, les modulateurs de glycosylation qui affectent la fixation des glycanes peuvent être de puissants outils pour développer des thérapies à base de glycane.

[0] Disrupted glycosylation of lipids and proteins isa cause of neurodegeneration. Tobias Moll, Pamela J. Shaw and Johnathan Cooper-Knock doi:10.1093/brain/awz358


Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Amyotrophic lateral sclerosis caused by mutations in the FUS gene is characterized by cytoplasmic FUS aggregates (FUS proteinopathy). Shelkovnikova et al. find that the antiviral immune response promotes FUS protein accumulation and its coalescence into persistent cytoplasmic assemblies. Viral infection can serve as a trigger of FUS proteinopathy in ALS.

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Mutations in the FUS gene cause familial amyotrophic lateral sclerosis (ALS-FUS). In ALS-FUS, FUS-positive inclusions are detected in the cytoplasm of neurons and glia, a condition known as FUS proteinopathy. Mutant FUS incorporates into stress granules (SGs) and can spontaneously form cytoplasmic RNA granules in cultured cells.

However, it is unclear what can trigger the persistence of mutant FUS assemblies and lead to inclusion formation. Although FUS readily aggregates in the test tube, this is not the case in vivo, and available rodent models expressing mutant FUS do not develop FUS aggregates in the CNS. This is a very different behavior from mutated proteins like SOD1, C9orf72 or TDP-43. While those last three proteins can aggregate, the reason why they aggregate are different for each of them but are related to instability in their shape. FUS proteinopathy is different.

Epidemiological and clinical evidence for a connection between viral infection and ALS has been accumulating for decades (Celeste and Miller, 2018; Ravits, 2005; Vandenberghe et al., 2010). For example, it is known that individuals with a history of poliomyelitis have a higher risk of developing motor neuron disease later in life (Martyn et al., 1988). Similarly, patients infected with HIV or human T cell leukemia virus 1 develop neurological disorders resembling clinical features of ALS (Alfa- had and Nath, 2013). Indeed one of the multiple biological roles of TDP-43 (which is the cause of most ALS cases) is to mitigate HIV infections. Importantly, multiple viruses are able to induce SG assembly (McCormick and Khaperskyy, 2017; White and Lloyd, 2012).

In the current study, Tatyana A. Shelkovnikova and her colleagues show that the exposure to foreign double-stranded RNA (dsRNA), typical for some viral infections, is a potent inducer of persistent FUS-enriched assemblies in the cytoplasm of cells expressing either exogenous or endogenous mutant FUS. Furthermore, they show that type I interferon (IFN), the central component of antiviral signaling, promotes accumulation of FUS protein. They propose that the antiviral immune response, with its profound effect on FUS levels and distribution, can serve as a trigger of FUS proteinopathy in ALS-FUS.


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.

Pour être efficace contre la maladie d'Alzheimer, il semble évident qu'un médicament doit pouvoir exercer un effet sur le cerveau. Mais selon les résultats présentés lors de la 12e conférence des essais cliniques sur la maladie d'Alzheimer, qui s'est tenue du 4 au 7 décembre à San Diego, en Californie, une thérapie pourrait également influencer le cerveau sans jamais pénétrer la barrière hémato-encéphalique.

L'apabétalone est une petite molécule administrée par voie orale, qui a été créée par Resverlogix Corp. Des chercheurs ont rapporté lors de la 12e conférence des essais cliniques sur la maladie d'Alzheimer que l'apabétalone semblait ralentir le déclin cognitif, mais seulement chez les personnes les plus atteintes et après une année d'administration.

L'apabétalone bloque essentiellement l'association entre BET et les lysines acétylées, écrasant la transcription de centaines de gènes. Auparavant, les chercheurs avaient rapporté que les protéines BET stimulaient l'expression d'une myriade de gènes impliqués dans l'inflammation, le métabolisme lipidique et la fonction vasculaire, faisant de l'apabétalone un traitement candidat pour les maladies cardiovasculaires et autres maladies chroniques du vieillissement.

De nombreux gènes ciblés par l'apabétalone se trouvent en aval du facteur de nécrose tumorale α (TNFα), un maître régulateur de l'inflammation. Les résultats présentés par Ewelina Kulikowski de Resverlogix, suggèrent que l'apabétalone pourrait atténuer les réponses inflammatoires provoquées par le TNFα, apaiser l'inflammation vasculaire - et peut-être même limiter l'activation chronique des cellules gliales de l'autre côté de la barrière hémato-encéphalique.

L'essai multicentrique de phase III BETonMACE était conçu pour déterminer si l'apabétalone en association avec des statines pouvait diminuer les événements cardiaques par rapport au traitement avec des statines seules.

Les participants à l'essai avaient un diabète de type 2, un syndrome coronarien aigu et de faibles niveaux de lipoprotéines de haute densité (HDL). L'essai s'est poursuivi jusqu'à 250 événements cardiovasculaires. Bien que le médicament ait eu tendance à réduire les événements cardiovasculaires, l'effet n'a pas atteint la signification statistique.

Sur les 2425 personnes inscrites à l'essai, 469 personnes de plus de 70 ans ont participé à une sous-étude cognitive, le Montreal Cognitive Assessment (MoCA). Alors que les scores MoCA ont légèrement diminué ou sont restés stables dans les groupes sous traitement et sous placebo parmi les participants des deux groupes à MoCA élevé, au contraire ceux dont les scores MoCA étaient les plus bas ont semblé bénéficier du traitement.

Parmi les 97 participants de ce sous-groupe, ceux prenant de l'apabétalone se sont améliorés en moyenne de trois points sur le test entre la ligne de base et 27 mois, tandis que ceux sous placebo, curieusement, se sont améliorés de 1 point. Les chercheurs pensent que le médicament atténue les troubles cognitifs en ciblant l'inflammation du système vasculaire.

L'idée qu'un endothélium vasculaire enflammé - en particulier dans les vaisseaux qui composent la barrière hémato-encéphalique - pourrait endommager la santé du cerveau et diminuer les capacités cognitives, confirme les résultats d'études précédentes.

For therapies aimed at Alzheimer's disease, it seems obvious that an effective drug must act on the brain. But according to the results presented at the 12th conference of clinical trials on Alzheimer's disease, which was held from December 4 to 7 in San Diego, California, a therapy could also influence the brain without ever penetrating the blood-brain barrier.

Apabetalone is a small, orally administered molecule that was created by Resverlogix Corp. Researchers reported at the 12th Alzheimer's Clinical Trials Conference that apabetalone appears to slow cognitive decline, but only in those most affected and after one year of administration.

Apabetalone essentially blocks the association between BET and acetylated lysines, crushing the transcription of hundreds of genes. Previously, researchers had reported that BET proteins stimulate the expression of a myriad of genes involved in inflammation, lipid metabolism and vascular function, making apabetalone a candidate treatment for cardiovascular and other chronic diseases of aging.

Many genes targeted by apabetalone are found downstream of the tumor necrosis factor α (TNFα), a master regulator of inflammation. The results presented at the conference by Ewelina Kulikowski of Resverlogix, suggest that apabetalone could attenuate the inflammatory responses provoked by TNFα, soothe vascular inflammation - and perhaps even limit the chronic activation of glial cells on the other side of the blood-brain barrier.

The BETonMACE multicentre phase III trial was designed to determine whether apabetalone in combination with statins could decrease heart events compared to treatment with statins alone.

Participants in the trial had type 2 diabetes, acute coronary syndrome and low levels of high density lipoprotein (HDL). The trial continued for up to 250 cardiovascular events. Although the drug tended to reduce cardiovascular events, the effect did not reach statistical significance.

Of the 2,425 people enrolled in the trial, 469 people over the age of 70 participated in a cognitive sub-study, the Montreal Cognitive Assessment (MoCA). While the MoCA scores decreased slightly or remained stable in the treatment and placebo groups among participants in the two high MoCA groups, those with the lowest MoCA scores appeared to benefit from treatment.

Among the 97 participants in this subgroup, those taking apabetalone improved on average by three points on the test between the baseline and 27 months, while those on placebo, curiously, improved by 1 point . Researchers believe the drug alleviates cognitive impairment by targeting inflammation in the vascular system.

The idea that an inflamed vascular endothelium - particularly in the vessels that make up the blood-brain barrier, could damage brain health and decrease cognitive ability, confirms the results of previous studies.

Disturbances in glucose metabolism (insulin resistance and abnormal glucose tolerance) are frequently observed among ALS patients. In recent years, there has been growing interest in the elusive relationship between premorbid diabetes and ALS.

With regard to the risk of developing ALS, studies in European countries have demonstrated that premorbid type 2 diabetes protects people against ALS development. One exception was the study by Sun et al. , who found that premorbid type 2 diabetes increased the risk of ALS development in Asia (Taiwan, China). In addition, a 4 year delay in the onset of ALS was observed in ALS patients with premorbid type 2 diabetes.

The aforementioned literature demonstrated the distinctive effect of premorbid type 2 diabetes on ALS patients from Asia and Europe. The present study aims to provide evidence for the association between premorbid type 2 diabetes and ALS by evaluating the onset and prognostic value in our cohort of ALS patients.

Patients were recruited from the national referral Amyotrophic Lateral Sclerosis Clinic at the Department of Neurology, Peking University Third Hospital (PUTH), Beijing, between 1January 2013, and 31 December 2016. Among 1331 consecutive sporadic ALS patients, 100 (7. 5%) were labeled as ALS type 2 diabetes and 1231 were labeled as ALS control according to the presence or absence of premorbid type 2 diabetes

As in other studies, the authors found a 4. 4 year delay in the onset of ALS inpatients with premorbid type 2 diabetes after controlling for other ALS disease modifiers, including gender.

The prevalence of premorbid type 2 diabetes at base line in ALS patients was lower than the estimated rate among the Chinese population. The overall prevalence of premorbid type 2 diabetes at baseline among ALS patients was 100/1331¼7. 5%; however, the expected prevalence of type 2 diabetes in the general population (>18 years) in China is estimated to be over 11. 6% (95% CI, 11. 3% – 11. 8%). This observation also indicates a protective role of premorbid type 2 diabetes on ALS development. This result was consistent with what has been reported in other studies.

In this study, the mean age of onset of ALS symptoms was 52. 9 years (SD, 10. 2 years), which was lower than that reported in Japan (64. 8 years), Italy (64. 8 years), Europe (64. 4 years) and Germany (67. 0 years). The age of onset of Chinese patients with ALS is approximately a decade younger than that of European and Japanese patients with ALS.

It is noteworthy that the willingness to medically treat younger patients is much stronger than that of elderly patients. Since ALS is a relatively rare disease, ALS might be under recognized in older people because being weak or wasted may be regarded as a normal part of aging or because multiple medical problems may ALS diagnostic difficult. This may create bias.

A clear molecular explanation of the relationship between type 2 diabetes and ALS remains a challenge. Recently, several radiographic and molecular studies have demonstrated that structural and functional alterations in the hypothalamic melanocortin system are frequently observed at the preclinical stage of ALS patients. The essential role of melanocortins lies in the regulation of body weight and appetite. The hypothalamic melanocortin pathway is a critical center for monitoring, processing, and responding to peripheral signals, including hormones, such as ghrelin, leptin, and insulin.

In ALS patients, these alterations in the structure and function of the hypothalamic melanocortin system provide a mechanistic explanation for the abnormalities in food intake and metabolism observed inpatients with ALS. Increasingly, behavior related changes have been associated with improved survival. Similarly, these preclinical alterations in the hypothalamic melanocortin pathway, as compensatory changes for ALS development, could also be a potential explanation for ALS patients with insulin resistance and type 2 diabetes. High levels of glucose could reduce the damage to motoneurons caused by hypermetabolism in the preclinical and early stages of ALS, while in the middle and late stages of ALS, when the melanocortin system is in a decompensatory period, insulin resistance and type 2 diabetes have no beneficial effect on the progression or survival of ALS patients.

In Alzheimer disease, for example, clinical and epidemiological studies have shown that the risk of Alzheimer disease was almost doubled in type 2 diabetes patients compared to the general population. Insulin deficiency and insulin resistance, core features of type 1 diabetes and type 2 diabetes, were also observed in the brains of Alzheimer disease patients. Thus, researchers proposed the term “type 3 diabetes”, which reflects the fact that Alzheimer disease represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes and type 2 diabetes. However, the question of whether the observed insulin resistance is a cause or consequence of neuro-degeneration in Alzheimer disease remains open.

Finally, the anti type 2 diabetes drugs metformin and pioglitazone, which have been proven to be neuroprotective in Alzheimer disease and other neurodegenerative diseases, have unexpectedly failed to show beneficial effects on the progression or survival of ALS patients. It was found that, at later time points, the metformin induced trophic effects may have been overshadowed by advancing and aggressive SOD1G93A pathology and potentially negative drug effects. The cause of pioglitazone’s failed clinical translation remains elusive. It was even suggested that suboptimal glycemic control may be beneficial in ALS.

Most neurodegenerative diseases are proteopathies. Alleviating ER stress is a promising approach for treating a range of diseases. Heren researchers aimed to identify a potent chemical chaperone through High-Throughput Screening of a small molecule chemical library.

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. For example Tudca (see AMX00035 trial) has some efficiency in this area. Tudca is a chemical chaperone.

Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Scientists have identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen.

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) is called ER stress. The cell has an adaptive system against ER stress called the unfolded protein response (UPR), which is the coordinated transcriptional upregulation of ER chaperones and folding enzymes that prevents the aggregation of unfolded and incompletely folded protein.

To overcome ER stress-related diseases, the following two pharmacological strategies can be applied: the modulation of ER protein folding environments (by UPR modulators) and a reduction in the accumulation of unfolded or misfolded ER proteins (by chemical chaperones).

In contrast, several chemical chaperones that have shown therapeutic benefits in mouse disease models have also been developed. 4-Phenylbutyrate (4PBA) and taurourso-deoxycholic acid (TUDCA) have been reported to function as chemical chaperones and have shown therapeutic benefits for a wide variety of diseases, such as diabetes, ALS and Alzheimer's disease.

Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, their data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.


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.

Amylyx Pharmaceuticals, Inc., a pharmaceutical company focused on developing new treatments for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, announced today that AMX0035 has demonstrated significant treatment advantage for people with of ALS in the CENTAUR study. In the study, participants taking AMX0035 had a statistically significant slowdown in the progression of ALS disease, as measured by the revised ALS functional rating scale (ALSFRS-R) compared to placebo.

AMX0035 is an orally available candidate therapy designed to minimize the mechanisms associated with nerve cell death. It is made up of two small molecules - tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate (PB) - which target signals in the mitochondria and endoplasmic reticulum of a cell, two compartments strongly involved in cellular stress and death of nerve cells.

TUDCA and PB have been shown to prevent cell death and damage neuroinflammation in preclinical models of ALS.

According to Justin Klee, co-founder and president of Amylyx, the therapeutic strategy followed is somewhat unique in that it does not try to prevent the root cause of ALS, the process of which, in most cases, has occurred since long before a person is diagnosed; rather, it aims to preserve motor neurons.

"What ultimately causes the clinical decline of ALS is that the motor neurons in the brain and spine degenerate and die," said Klee. "What we designed was that if we could identify or develop a therapy that could intervene in cell death and degeneration, then maybe we could have a therapy that would work for ALS, as well as neurodegeneration as a whole. "

CENTAUR participants had the opportunity, after the trial, to enroll in an open-label extension study to receive treatment with AMX0035. Almost 90 percent of participants who have completed CENTAUR have chosen to enroll in the extension study. Intermediate data from the ongoing extension study will be presented in 2020.

Sabrina Paganoni, MD, PhD, Harvard professor leading the trial, explained that CENTAUR was designed to maximize the data that could be obtained using the least number of participants and in the least possible time. This involved the use of stringent enrollment criteria - essentially, only those individuals who were expected to have the most severe ALS with the fastest disease progression, were enrolled. "In other words, when we test the drug in the most severe patients - those who need it most - if we can stop or slow the disease in these patients, we expect to do the same in all patients . "

Paganoni added that if AMX0035 reaches the point of being approved by regulatory authorities for the treatment of ALS, it should be approved for all patients with ALS.

In addition, the company will provide an update on regulatory plans and more details on expanded access plans in early 2020.

Dr. Rudolph Tanzi, Ph.D., Professor Kennedy of Neurology, Massachusetts General Hospital, Chairman of the Cure Alzheimer's Fund research leadership group and Chairman of Amylyx SAB, shared: "The positive results of the CENTAUR study ALS demonstrate that the mechanism of AMX0035 could represent a new therapeutic approach not only for ALS, but for Alzheimer's disease. I am very excited about the proven benefits of AMX0035 in people with ALS and look forward to the results of the ongoing PEGASUS trial for people with Alzheimer's disease. "


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.

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