Posts tagged: ALS - Padirac Innovations' blog

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases characterized by the presence of neuropathological aggregates of phosphorylated TDP-43. The TDP-43 protein is also a component of stress granules. Stress granules are cytoplasmic vesicles that form when a cell experiences intense stress conditions. Under these conditions the cell considerably reduces its production of proteins.

So almost all of the studies aiming at reproducing TDP-43 inclusions have been carried out under conditions of intense short-term stress, which differ significantly from the chronic stress conditions occurring in neurodegeneration.

In addition, most of the studies have been done using immortalized cell lines, which are very different from natural cells.

In the article which is the subject of this post and which was posted on the pre-print server BioRxiv, the authors show that a state of mild but prolonged oxidative stress, leads to the formation of stress granules in primary fibroblasts and neurons derived from iPSC in both controls and ALS patients.

In their experiment, primary fibroblasts and neurons derived from induced pluripotent stem cells from ALS patients carrying mutations in the TARDBP (n = 3) and C9ORF72 (n = 3) genes and healthy controls (n = 3) were exposed to oxidative stress by sodium arsenite.

The formation of stress granules and the cellular response to stress were evaluated and quantified by immunofluorescence and electron microscopy analyzes. The scientists found that not only an acute, but also a chronic oxidative insult, is capable of inducing the formation of stress granules in primary fibroblasts and neurons derived from iPSC.

The researchers assume that, when stress is chronic, as in neurodegeneration, cells carrying a TARDBP mutation show less capacity to induce a long-term protective mechanism, unlike C9ORF72 mutant cells.

Above all, the authors of the article observed the recruitment of TDP-43 in stress granules and the formation of phosphorylated aggregates of TDP-43, very similar to the abnormal inclusions observed in the autoptic ALS / FTD brains, this only in case of chronic stress. In addition, in fibroblasts, the cellular response to stress was different in control compared to mutant ALS cells, probably due to their different vulnerability.

A quantitative analysis also revealed differences in terms of the number of cells forming stress granules and the size of stress granules, suggesting a different composition of the vesicles in acute and chronic stress.

In prolonged stress, the stress granules and the formation of phosphorylated TDP-43 aggregates were concomitant with an increase in p62 and deregulation of autophagy in ALS fibroblasts and iPSC-derived neurons. This alteration in autophagy suggests that prolonged stress alters the cellular mechanism of protein degradation and reduces the ability of stress granules to disassemble properly.

The authors of the article assume that in neurodegeneration, there is a critical stress threshold above which the disassembly of stress granules becomes impossible and causes the quality control of system proteins, including chaperones, to be engulfed, and the autophagic and ubiquitin / proteasome systems.

Cells derived from ALS patients, exposed to persistent oxidative stress, represent an appropriate bioassay to study not only the pathology of TDP-43, but also to test potential drugs capable of preventing or breaking down phosphorylated inclusions of TDP-43 .


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.

For anyone studying research against neurodegenerative diseases, it is striking to note the large number of studies which each claim to have identified a key element, different in each study, and which would be a causative factor of the disease. In addition, many studies are contradictory with each other.

In epidemiology, Mendelian randomization is a method of using measured gene variation, known to express the causal effect of exposure to a disease in observational studies, without the need for a traditional randomized clinical trial. Even better, it allows us to escape traditional biases in epidemiological studies, such as reverse causation and confusion. This method was first proposed in 1986 by Gray and Wheatley.

Since genotypes are randomly assigned when passed from parents to offspring during meiosis, the distribution of the population genotype should not be linked to the confounding factors that generally affect observational epidemiological studies. In this regard, Mendelian randomization can be viewed as a randomized controlled trial.

Because polymorphism is the instrument, Mendelian randomization depends on previous genetic association studies that have provided good candidate genes for the response to risk exposure.

Each of these selected genetic variants must satisfy three conditions, relevance, independence, exclusion restriction.

Among the various genetic and environmental factors that have been identified to be associated with ALS, the association between blood lipid metabolites and ALS has recently received considerable attention. The associations between lipids and ALS are strong and comparable in strength to many risk factors for ALS previously identified.

ALS patients suffer from increased energy expenditure at rest and from weight loss. Previous observational studies have shown that ALS patients frequently experience dyslipidemia. Dyslipidemia is characterized by abnormal levels of high density lipoproteins (HDL), low density lipoproteins (LDL), total cholesterol (TC) and triglycerides (TG).

The positive association between dyslipidemia and ALS suggests that elevated levels of non-HDL lipids may play a protective role in the progression of ALS. Consistent with observational studies in humans, research with ALS mouse models has also shown that the overall survival of ALS mice is reduced under calorie restriction. However, the relationship between dyslipidemia and ALS is also controversial, conflicting results have been reported for basal serum lipid levels, the cause of dyslipidemia, and the relationship between serum lipid levels and the progression of ALS disease.

For example, many observational studies following ALS have found no association between dyslipidemia and ALS. In addition, some studies have shown that patients with ALS often suffer from hypolipidemia - which is mainly characterized by low levels of LDL - in men and women with ALS. The association between hypolipidemia and ALS is further confirmed in a mouse ALS model. The conflicting results on the relationship between lipid levels and ALS may be due in part to the relatively small sample sizes used in previous studies and in part to uncontrolled confounders that are inevitable in observational studies .

Determining the causal impact of lipids on ALS is difficult using traditional randomized controlled trial studies because these studies necessarily require long-term follow-up, are expensive and often unethical. Therefore, it is desirable to determine the causal relationship between lipids and ALS through observational studies. Mendelian randomization is a powerful statistical tool for examining the causal relationship and estimating causal effects in observational studies.

Scientists have studied the causal effects of four blood lipid traits on the risk of ALS:

  • high density lipoprotein,
  • low density lipoprotein (LDL),
  • total cholesterol,
  • triglycerides.

The authors first selected SNPs (genetic variants) which can serve as valid instrumental variables for each of the four lipid traits (HDL, LDL, TC and TG).

Taking advantage of the instrument variables from several large-scale association studies on the genome in European and Asian populations, the authors performed one of the most important and comprehensive Mendelian randomization analyzes to date on the causal relationship between lipids and ALS. Among the four lipids, they found that only LDL is causally associated with ALS and that a higher level of LDL increases the risk of ALS in European and East Asian populations.

The large sample size used in this study allows the authors to fully establish a positive causal effect of the modifiable factor LDL on ALS in European and East Asian populations. The inferred causal relationship between LDL and ALS is robust in the choice of statistical methods and is carefully validated by various sensitivity analyzes.

The positive causal effect of LDL on ALS suggests that future development of strategies to reduce LDL levels would likely reduce the burden of ALS. LDL is a modifiable risk factor, the levels of which can be reduced by various intervention strategies. For example, dietary changes such as increased fiber intake, increased phytosterol consumption, and increased consumption of nuts can all lead to a reduction in LDL levels.

Restrictions on dietary cholesterol, restrictions on high-carbohydrate diets, and restrictions on the consumption of trans fats can also lower LDL levels. In addition to lifestyle and dietary changes, LDL reduction can be achieved by drug therapy.

This is not a breakthrough regarding the mechanism of onset of the disease, but it introduces a tool for managing this disease.

The future development of LDL reduction strategies and the development of public policies to promote such strategies are likely to reduce the burden of ALS in society.


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.

Scientists from UK and Taiwan have developed a modeling platform at the cellular level, which summarizes the key aspects of sporadic ALS and demonstrates both an initial neuroprotective role for astrocytes and the cell-type specific toxic effect of TDP-43 oligomers.

A key pathological feature of ALS is the cytoplasmically poorly located and aggregated TDP-43 protein in at least 95% of cases. Research on ALS has spanned more than 20 years, primarily focused on the genetic aspects of ALS, which however only account for approximately 10% of cases. This has the remaining 90% of sporadic ALS cases relatively little studied. In addition, and despite considerable investment in genetic research, the most common gene for ALS (C9orf72) was only discovered in 2011.

The role of non-neuronal cells (glial cells) has also been neglected for a very long time. First because we thought that their role was limited to metabolism and the maintenance of synapses, then because it is much easier to understand what little use a neuron which often connects two distant points of the nervous system, only cells that only seem to have a local role. Today we know that these cells are as important as neurons for mental processes, and that microglia play the role of the immune system in the nervous system. Among these cells are astrocytes and their relationship with the TDP-43 pathology is not yet well understood at present.

The authors of the study that is the subject of this post therefore used motor neurons and astrocytes derived from human-induced pluripotent stem cells (iPSC) to model the specific characteristics of motor neurons in sporadic ALS.

The authors exposed its human iPSC-derived motor neurons to tissue extracts from sporadic ALS patients and observed that the TDP-43 protein aggregated in the cytoplasm of these motor neurons. Contrary to what had been achieved in previous studies, aggregation was obtained with very low concentrations of TDP-43. We can therefore speak of seeding, a characteristic of prion diseases.

Next, the authors showed that motor neurons derived from human iPSC are more vulnerable to the aggregation and toxicity of TDP-43 than their astrocyte counterparts. These TDP-43 aggregates can spread from motor neurons to astrocytes. The authors, however, discovered that astrocytes are capable of reducing poorly localized cytoplasmic TDP-43 and cell toxicity.

In summary, these scientists detected TDP-43 oligomers in these spALS spinal cord extracts, and demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this specific cell-type toxicity, providing additional support for a hypothesis of mediated toxicity. by protein oligomers in ALS, i.e. prion-like behavior.


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.

The article reported here discusses gene therapy for ALS by intervention in the peripheral nervous system. Although this has already been done with good results, including in the central nervous system, this type of intervention has been very rarely experienced.

In sporadic as in familial ALS, the loss of motor neurons leads to muscle atrophy, accompanied by fasciculations and spasticity.

The mechanisms underlying the development of ALS in motor neurons are probably multifactorial and neighboring cells, such as microglia, astrocytes and interneurons, can contribute to the disease.

There is a controversy about the onset of ALS which going on since decades. Most scientists believe that it begins in the brain, precisely in the primary motor cortex, in the body of the higher motor neurons. This assumption is called "dying forward". However, other scientists believe that ALS begins at the other end of the motor pathway, possibly in the neuromuscular junction, or even in the muscles. This assumption is called "dying backward".

Although these two hypotheses seem contradictory, each has strong experimental support and neither has been conclusively refuted. Perhaps these two hypotheses represent different subtypes of ALS. The article discussed here supposes that the hypothesis of "dying back" is true so the authors present an intervention in the PNS.

The authors use a classical mouse model of ALS: SOD1G93A. This model animal exhibits the most common clinical and pathological features of ALS as well as rapid and severe progression of the disease.

As has been recently reported on Padirac Innovation, gene therapy has become very important in the context of ALS.

Furthermore, a currently promising therapy consists of in vitro modification and reimplantation of cells generating growth factors (Nurown).

Neuregulins or neuroregulins are a family of four structurally related proteins that are part of the EGF protein family. These are growth factor proteins. They have various functions in the development of the nervous system and play multiple essential roles in the embryogenesis of vertebrates, in particular: cardiac development, differentiation of Schwann cells and oligodendrocytes, certain aspects of neuronal development, as well as the formation of synapses neuromuscular.

Neurotrophic factors derived from spliced ​​forms of neuregulin 1 (NRG1) have been shown to be essential for the survival of motor neurons, supporting axonal and neuromuscular development and maintenance. However, the exact role of NRG1-I is not fully understood.

It has been reported (Mancuso et al., 2016) that the expression of NRG1-I by Schwann cells is essential for promoting axonal regeneration and remyelination. Indeed, the overexpression of NRG1-I by means of an AAV vector, injected locally into the gastrocnemius muscle produced a functional improvement by improving the collateral germination of the motor axons in SOD1G93A mice.

Given these recent discoveries, the authors aim here to overexpress humanized NRG1-I in all skeletal muscles by using gene therapy vectors to maintain motor innervation in SOD1G93A mice.

Interestingly, they found that overexpression of NRG1-I in muscles activates cell survival pathways via PI3K / AKT not only in this tissue, but also in the spinal cord, promoting better motor neuron survival and attenuation of reactivity of astrocytes and microglia.

Overexpression of NRG1-I increased ErbB receptors in skeletal muscles and their downstream pro-survival signaling. Signaling from the ErbB family of proteins is important during development. For example, the lack of maturation of Schwann cells leads to a degeneration of motor and sensory neurons. Excessive ErbB signaling is, however, associated with the development of a wide variety of solid tumor types.

Consequently, while NRG1-I could have a deleterious role during an upregulation in the spinal cord of SOD1G93A mice (Song et al., 2012), overexpression of NRG1-I improved the maintenance of neuromuscular function and innervation in SOD1G93A transgenic mice.

Since the pathogenesis of ALS is considered in the framework of the "dying backward" hypothesis, to develop in a process where the nerve endings and neuromuscular junctions are partially degraded while the cellular bodies (motor neurons, interneurons and glial cells) of the spinal cord are still intact, NRG1-I virally mediated therapy may be an appropriate approach to counter this initial degenerative process in motor neuron diseases.

However, further experiments are needed to elucidate the pathways modulated by overexpression of NRG1-I in skeletal muscle.

The mice were euthanized at 16 weeks, which is far too soon to draw conclusions about the long-term course of the therapy. Although it is clear that the treated mice experienced a much slower development of their disease, there was no remission.

There is also might be concern about the effects of excessive ErbB signaling on the risk of developing cancer.


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.

Bloom Science is a biotechnology company developing orally-delivered pharmaceutical therapies of specific microbiome. The company had demonstrated that specific strains of commensal microbes can act synergistically to upregulate the inhibitory neurotransmitter GABA in the brain by acting through the gut-brain axis with naturally-evolved pharmacology. enter image description here Bloom Science signed an agreement with Duke University, granting it an exclusive license related to libraries of genetic variants of Akkermansia genus bacteria developed in the laboratory of Raphael H. Valdivia. Raphael H. Valdivia, PhD, professor of molecular genetics and microbiology at Duke University will be joining Bloom as a scientific founder.

Akkermansia muciniphila is a species of human intestinal mucin-degrading bacterium. Extensive research is being undertaken to understand its association with obesity, diabetes, and inflammation.

Several observations suggest that the interface between the host and the gut microbiome may be altered in mouse models of ALS. Analysis of 16S ribosomal DNA (rDNA) from stool samples of patients with ALS yielded conflicting results: one study noted dysbiosis in 6 patients with ALS compared with 5 healthy controls, whereas another showed no differences between 25 patients with ALS and 32 healthy controls.

In mid 2019 a Nature article showed that altered gut microbiome worsens ALS symptoms in mice models of this disease. The authors also found that treatment with antibiotics exacerbates motor symptoms in an ALS mouse model, something that patients have suspected for a long time. They tested 11 strains: Eggerthella lenta, Coprobacillus cateniformis, P. goldsteinii, L. murinus, P. distasonis, Lactobacillus gasseri, Prevotella melaninogenica, Eisenbergiella tayi, Subdoligranulum variabile, R. torques and A. muciniphila (Akkermansia muciniphila).

In contrast to all of the other tested strains, treatment of Sod1-Tg mice models and wild-type mice with an anaerobically mono-cultured Akkermansia muciniphila strain, was associated with improved motor function in Sod1-Tg mice. Indeed those Sod1 mice model may have suffered from the antibiotic "washing" that they endured to kill their microbiome, so probably the gain of function is difficult to quantify. The Sod1 mice treated with Akkermansia muciniphila, lived 10 days longer that non treated mice, a 6% improvement, and they displayed less ALS symptoms.

On contrary Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS.


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.

Scientists in South-West of Germany, have investigated the associations of serum concentration of insulin-like growth factor 1 (IGF1) with prognosis of ALS in their region ALS registry in a case-control and cohort study, respectively.

Their study showed a clear association of low serum IGF-1 concentration with the prognosis of ALS, suggesting that higher IGF-1 concentration could increase survival.

There is growing evidence that a disturbed energy metabolism in ALS could play a pathogenic role. Data from Swabia's ALS registry showed a possible positive association of body mass index (BMI) with ALS decades before the clinical manifestation of ALS. In the ALS cases, there was a sharp kink in BMI trajectories shortly before onset of ALS, and greater weight loss was associated with a worse prognosis.

Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor with multiple functions in the peripheral and central nervous system. It supports neuronal survival and axon growth. IGF-1 led to increased survival of ALS patients in most but not all studies. It has also been the subject of several positive clinical trials, but it has undesired side effects. However results of a recent trial on IGF-1 in the treatment of spinal and bulbar muscular atrophy (SBMA), a rare motoneuron disease of the peripheral muscle with slow progression, did not improve muscle strength or function20.

The objective of this study was to analyze the associations of serum IGF-1 concentrations with the risk of ALS in a population-based case-control study. Furthermore, they investigated the association of IGF-1 serum concentration with prognosis of ALS in a cohort-design in ALS-cases only.

The ALS registry Swabia is a population-based clinical-epidemiological registry with the aim to collect data on all newly diag-nosed ALS cases in Swabia, a defined geographic region with approximately 8.4 million inhabitants in the South-West of Germany.

In this population-based case-control study in Southern Germany, serum IGF-1 concentrations were not associated with risk of ALS. In the cohort of ALS patients, however, they found evidence for an inverse association between high serum IGF-1 concentrations and overall survival. their results in the ALS cohort concerning prognosis are in line with observations of others.

Their observation that higher IGF-1 concentration is associated with longer survival is consistent with experimental research, showing that IGF-1 acts as a mitochondrial protector in the ALS cell and mouse model.

Multiple mechanisms elicited by IGF-1 might account for the observed increased survival in patients with higher circulating IGF-1. IGF-1 displays high neurotrophic properties, which could protect motor neurons and increase survival in ALS25. IGF-1 has also anabolic actions on skeletal muscle, especially upon denerva-tion26, which might be beneficial in ALS. Since IGF-1 is also related to energy metabolism and body weight, their current findings are consistent with former observations concerning BMI and adipokines as well as the findings on retinol binding protein (RBP)4 and the prognosis of ALS.

However, the observed protective effect of higher IGF-1 was observed upon adjustment of BMI, suggesting that it is not fully mediated by BMI as marker for fat mass. Thus, the longer survival of patients with higher IGF-1 levels could be related to direct biological actions of IGF-1, to an overactivation of a protective GH-IGF-1 pathway or to altered IGF-1 levels in patients with a favorable metabolic status.

So very high values IGF-1 are associated with a better prognosis of ALS suggesting that biological functions related to IGF-1 could be involved in ALS survival.


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.

HDAC inhibitors has been proposed since some time for ALS. They have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they were being investigated as possible treatments for cancers, parasitic and inflammatory diseases.

Sodium valproate an HDAC inhibitor, had been tested for ALS in clinical trial, it was quite effective but there were severe side effects. Another trial will soon combine it with lithium.

A team [0] tested in-vitro several other HDAC inhibitor and found that two of them, SAHA, RGFP109, when combined with arimoclomol did reduce the loss of nuclear FUS (In ALS-FUS, FUS localizes in cell's cytosol instead of the nucleus, in a similar manner to TDP-43's behavior). They also found that HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUS P525L mutation.

They evaluated the ability of different classes of histonedeacetylase inhibitors to enable the heat shock response inmotor neurons, both alone and in combination with drugs that induce HSP expression constitutively or magnify induction in stressed cells (co-inducers)

It is still unknown if compounds with more substantial HDAC inhibitory activity will enhance the heat shock response, or the mechanisms regulating HSP expression.



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.

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 ''.

enter image description here

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.

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.

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.

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