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A new study published Jan. 21 in Nature by Katrin Andreasson and Paras Minhas, suggests that cognitive aging is not irrevocable, but can be reversed by reprogramming glucose metabolism in myeloid cells.

Biologists have long hypothesized that reducing inflammation may slow down the aging process and delay the onset of age-associated diseases, such as heart disease, Alzheimer's disease, cancer and the frailty that concerns each of us during our aging. Yet, the question of exactly what causes these inflammatory reactions of the immune system had not found a definitive answer.

Diseases concerned

A long-standing observation in epidemiological studies of aging populations has been that NSAIDs, which inhibit the production of cyclooxygenase-1 (COX-1) and COX-2 and prostaglandin (PG), prevent the development of the disease. Alzheimer's.

Model ALS mice and patients with sporadic ALS have increased levels of prostaglandin E2 (PGE2). In addition, levels of microsomal proteins PGE synthase-1 and cyclooxygenase-2, which catalyze PGE2 biosynthesis, are dramatically increased in the spinal cord mice model of ALS .

Preclinical studies suggest that prostaglandin E2 (PGE2) is an essential inflammatory mediator of brain damage via the activation of four G protein coupled receptors, namely EP1-EP4.

Transient inhibition of the EP2 receptor by antagonists permeable to the blood-brain barrier shows marked anti-inflammatory and neuroprotective effects in several rodent models of epilepsy, without, however, having a noticeable effect on seizures per se.

In the brain, microglia lose the ability to remove misfolded proteins associated with neurodegeneration.

Prostaglandin and myeloid cells

Prostaglandins are one of the main mediators of inflammation which play an important role in improving neuroinflammatory and neurodegenerative processes. Myeloid cells are the main source of PGE2, a hormone belonging to the prostaglandin family. Prostaglandins are a group of physiologically active lipid compounds derived from arachidonic acid.

Arachidonic acid is one of the most abundant fatty acids in the brain (10% of its fatty acid content). Among other things, it helps protect the brain from oxidative stress by activating the gamma receptor activated by peroxisome proliferators.

One type of receiver for PGE2 is EP2. This receptor is found on immune cells and is particularly abundant on myeloid cells. It initiates inflammatory activity inside cells after receiving PGE2.

Myeloid and macrophages

Myeloid cells are distinguished from lymphocytes. Monocytes, a type of myeloid cell, and their macrophages and dendritic cell descendants perform three main functions in the immune system. These are phagocytosis, antigen presentation and cytokine production.

Macrophages engulf and digest cell debris, foreign substances, microbes, cancer cells, and anything that does not have the type of proteins specific to healthy cells in the body on its surface. The first author of the study, Paras Minhas, initially isolated monocytes from blood donated by healthy people under the age of 35 or over 65. Scientists also looked at macrophages from young mice compared to old mice.

During aging, functional changes are due to macrophages. Microglia residing in the brains of aged mice increase their soma volume but reduce the length of their processes, limiting their ability to interact and support neuron survival.

Macrophages can undergo "training" after re-exposure to a stimulus. Recent studies have described that the induced immunity in young mice leads to an increase in myeloid lineage cells and can occur in myeloid precursors in the bone marrow. As we age, a similar shift towards a myeloid cell line occurs, and the aging microenvironment may also have a ripple effect.

Effects of a significant increase in PGE2 levels

The authors observed that older macrophages from mice and humans not only produced significantly more PGE2 than in younger subjects, but also had a much higher number of EP2 on their surface. Andreasson and his colleagues also confirmed significant increases significant levels of PGE2 in the blood and brain of old mice. The researchers found that in aging macrophages and microglia, PGE2 signaling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flow and mitochondrial respiration.

The dramatically increased PGE2-EP2 binding in elderly myeloid cells alters energy production in these myeloid cells by inducing them to store glucose, rather than fueling energy production in the cell. Cells store glucose by converting this energy source into long chains of glucose called glycogen (the animal equivalent of starch).

This build-up creates a state of chronic exhaustion (stress) in the cells, which leads them to express inflammatory signals. Not only have aging macrophage cells found it difficult to burn glucose, they also don't use other sources of energy for respiration. Young macrophage cells were better able to utilize lactate and pyruvate.

An apparent rejuvenation?

The authors deleted EP2 in transgenic mice, which halved the amounts of receptors. Macrophages from 20 month old EP2-deficient mice maintained normal cellular respiration and glycolysis. In control animals of the same age, macrophage function deteriorated with age. Cells from control animals secreted pro-inflammatory factors, were poorly phagocytosed, and had fewer and poorly formed mitochondria. Macrophages deficient in EP2, on the other hand, had none of these problems, behaving like those of young mice.

Scientists gave mice one or both of two experimental drugs known to interfere with PGE2-EP2 binding in animals for a month. They also incubated cultured mouse and human macrophages with these substances. In doing so, the old myeloid cells metabolized glucose just like the young myeloid cells, reversing the inflammatory character of the old cells.

More strikingly, the drugs reversed the cognitive decline associated with the age of mice. Indeed, the old mice who received them performed recall and spatial navigation tests as well as the young adult mice. Blocking peripheral myeloid EP2 signaling is therefore sufficient to restore cognition in aged mice.

The blood-brain barrier EP2 inhibitor C52 improved glycogen synthesis, improved glycolytic response and TCA cycling of myeloid cells (microglia and peripheral macrophages), and improved cognitive performance.

Surprisingly, mice reaped these cognitive benefits even when treated with an EP2 inhibitor (PF-04418948) that does not cross the blood-brain barrier.

Towards drugs?

Since activation of the EP2 receptor has been identified as a common culprit in several neurological conditions associated with inflammation, such as stroke and neurodegenerative disease, selective small molecule antagonists targeting EP2 are being developed. to suppress PGE2-mediated neuroinflammation.

Several companies manufacture selective EP2 antagonists, but none are approved for human use. Pfizer's PF-04418948 was tested for safety in a Phase 1 study in 2010, but the company has discontinued clinical development.

However, targeting EP2 could be complicated. The receptor is known to regulate blood flow and blood pressure, and has been shown to protect the brain during stroke.

A study was recently reported in the press as showing promise for a cure for ALS. Although the content reported by the press is accurate, the interpretation by members of the ALS community is wrong: There is no way (yet) to cure ALS, but on the other hand the study reinforces and clarifies the long-suspected link between ALS and metabolism.

About 10 to 20% of cases of amyotrophic lateral sclerosis are familial, with the C9orf72 mutation being the most common cause of familial ALS. The pathological mechanisms of the C9orf72 mutation in ALS remain unclear. Indeed, the loss of function induced by a mutation of C9orf72 alone does not contribute to the deficits of lysosomal rapid axonal transport in C9orf72 motor neurons derived from stem cells.

Enormous energy needs The processes involved in the functioning of motor neurons are all very energy consuming, which raises the question of whether alterations in energy metabolism contribute to defective axonal transport. Apart from alterations in the microtubule machinery observed in a rare mutation causing ALS: FUS, until the present study, however, it had not been shown that the metabolism of motor neurons from ALS patients differed from those of healthy motor neurons.

OXPHOS is the metabolic pathway of mitochondria For their energy supply, neurons, unlike astrocytes, are primarily dependent on mitochondrial oxidative phosphorylation. Oxidative phosphorylation (or OXPHOS) is the metabolic pathway in which cells use enzymes to catalyze the oxidation of nutrients, releasing the energy needed to form ATP. In almost all aerobic eukaryotes, oxidative phosphorylation takes place within the mitochondria. During oxidative phosphorylation, electrons are transferred from electron donors to electron acceptors, such as oxygen, via redox reactions. These redox reactions release energy which is used to form ATP. This is a very efficient route for generating energy, compared to other processes using fermentation such as anaerobic glycolysis.

The importance of energy from mitochondria in axonal transport The extraordinary length of motor neuron axons - 20,000 times longer than the diameter of their soma - suggests a particular metabolic vulnerability of motor neurons to deficits in key processes involved in maintaining axon form and function.

The transport of mitochondrial cargo, unlike vesicular transport, depends on the availability of mitochondrial ATP. Defective transport of the cargo to the distal axon has been reported in several types of ALS, and not just in genes involved in the transport of proteins in the axon. It is well established from animal models of ALS that axon targeting results in delay in disease progression and improved survival and that prevention of motor neuron loss only, but not axonal degeneration, is insufficient to promote patient survival.

Demonstration of a modified axonal transport To better understand this question, the scientists studied induced pluripotent stem cell lines derived from autopsy of patients containing the most common mutation causing ALS, C9orf72. These stem cells have been matured into motor neurons. They then demonstrate that motor neurons affected by the C9orf72 mutation have (in vitro) shorter axons, an axonal transport of the mitochondrial cargo which is altered and a modified mitochondrial metabolism.

The scientists then show that this deregulation is selective for the spinal (motor) neurons of the anterior horn, and is absent in the spinal (sensory) neurons of the dorsal horn (deregulation in the spinal motor neurons of the ventral horn, but not in sensory neurons of the corresponding dorsal horn).

Gene therapy manipulating PGC1α restores a good phenotype of mutated motor neurons and their axons The scientists then carried out by gene therapy an alteration of the genome of the mitochondria in the motor neurons carrying the C9orf72 mutation which are derived from stem cells. This alteration of the genome corrected the metabolic deficit and also saved axonal length and transport phenotypes.

The scientists were able to stimulate mitochondrial function (and biogenesis) through the manipulation of its main regulator, PGC1α, leading to the rescue of axonal phenotypes, providing a new mechanical link between mitochondrial bioenergetics. and axonal dysfunction.

A link with TDP-43? These data suggest that targeting the PGC1α pathway may be highly relevant for neurodegeneration, as it is possible that there are other mechanisms leading to axonal dysfunctions observed in motor neurons with the C9orf72 mutation. For example, recent findings show that the repeated proteins of the C9orf72 dipeptide can lead to cytoplasmic aggregation of TDP-43. Thus, the pathology of TDP-43, observed in the vast majority of ALS cases, including C9orf72, modulates mitochondrial homeostasis by regulating the processing of mitochondrial transcriptions.

Conversely, TDP-43 exerts a toxicity by penetrating into the mitochondria and by specifically altering the OXPHOS I complex and by inhibiting its translation which causes mitochondrial dysfunction.

Finally, recent work from Onesto et al. showed that there is compensatory mitochondrial biogenesis, as evidenced by the upregulation of PGC1α, in dermal fibroblasts derived from patients with the C9orf72 mutation in ALS.

This suggests that despite the deleterious effects of the mutation, most cell types can compensate for mitochondrial dysfunction by stimulating biogenesis. The specific vulnerability to motor neurons could result in part from an inability of motorneurones to modulate this homeostatic mechanism when they face too much energy expenditure.

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

Today we will present a BioRxiv preprint which has an indirect but interesting link to neurodegenerescence.

By using wavelet transform analysis Sánchez-Moguel et al report that the elderly with excess in theta activity show a higher energy in delta, theta, and alpha bands during the categorization of stimuli in a counting Stroop task. enter image description here Source Vanderbit.edu/Daniel Levin

Their findings imply that this increase neuronal activity might be related to a dysregulated energy metabolism in the elderly with theta excess that could explain the progress to cognitive impairment in this group.

The wavelet analysis allows them to have a standard frequency decomposition of EEG signals over time. So it can help to know the amount of energy used during the execution of Stroop tasks. enter image description here Source WIkipedia/Gerhard Rigoll

Healthy aging is accompanied by a natural detriment of physical and cognitive abilities. In particular, inhibitory control and attention are affected. The general objective of this study was to explore, using Wavelet transform, if there were differences in the amount of energy during the performance of a counting Stroop task between a group of elderly with an excess of theta activity in their EEG and a group of elderly with normal EEG. The specific objective was to evaluate the amount of energy between EEG groups for each of the frequency bands (i.e., delta, theta, alpha, beta, and gamma) across different time windows.

The researchers expected to find higher energy in the group with theta excess, specifically in the time window associated with categorization of stimuli. Changes in brain electrical activity, which can be measured noninvasively by the EEG, are tightly related to cognitive processes. Some authors have proposed that changes in the EEG of the elderly, obtained under resting conditions, are not only the result of normal aging but can contain signs of undergoing subclinical pathologic processe.

Moreover, excess in delta and theta band frequencies of resting EEG from healthy elderly, compared to a normative base according to age, is an excellent predictor of cognitive detriment in the following seven years.

Stroop tasks have been used during functional magnetic resonance imaging (fMRI) to study the decrease in the efficiency of inhibitory processing during healthy and pathological aging. In the counting Stroop task, subjects are asked to answer how many words are presented in a slide, regardless of the meaning of the word itself. Subjects increase their response times and tend to make more mistakes when the meaning of the word does not match the number of times that the word appears; this phenomenon is known as the Stroop or interference effect.

An over-recruitment of neuronal activity during aging was observed using fMRI during the execution of Stroop tasks; this enhanced neuronal activity is proposed to have a compensatory function. Furthermore, fMRI studies showed higher brain activity in older people with mild cognitive impairment compared to healthy elderly.

The main advantage of wavelet analysis over Fourier analysis is that they can follow the brain frequency dynamics over time.

The energy analysis using wavelets showed that during the execution of the Stroop task 1. Theta-EEG group assigns a greater amount of total energy in delta, theta, and alpha bands than the Normal-EEG group. 2. Theta-EEG group demands a higher amount of relative energy in delta band but less energy in beta and gamma bands than the normal-EEG group. 3. Theta-EEG group uses higher total energy in all-time windows in the delta, theta, alpha, and beta bands. 4. In the theta and alpha bands, the energy is greater in the Theta-EEG group.

The researchers propose that this excessive energy expenditure in the Theta-EEG group is due because more neurons are recruited in order to perform the task with the same efficiency as the Normal-EEG group. However, they do not know if this energy expenditure is due to cellular and metabolic imbalances that promote progress to cognitive impairment.

Imaging techniques such as fMRI, diffusion tensor imaging, and magnetic resonance spectroscopy, that evaluate the neural networks involved in the task and metabolic expenditure, would complement the findings of the article authors.

It has been suggested that autophagy insuficiency occurring during aging may contribute to increase of misfolded proteins. TDP-43 aggregates in motor neurons are found in the majority of ALS patients and in other neurodegenerative diseases. TDP-43 protein is involved in the regulation of RNA processing and splicing as well as in chromatin condensation.

In this article Sunny Kumar in Jean-Pierre Julien's lab in Laval's university, studied the translational profiles of neurons in one-year old transgenic mice expressing hTDP-43 A315T mutant, a model of ALS/FTD.

Dr. Jean-Pierre Julien’s is also ImStar Chief Scientific Officer research.

Measuring RNA from a defined subset of cells derived from a complex tissue is a challenge. The RiboTag method allows for immunoprecipitation of ribosome-associated RNA from specific cells within complex tissues .

Neurofilaments are major cytoskeletal components in neurons. Neurofilament disorganization can contribute to neuronal dysfunction and death. Transgenic mouse studies have highlighted the importance of Neurofilament protein stoichiometry for correct assembly and transport. Previous reports showed that TDP-43 can bind and stabilize Neurofilament mRNAs.

Kumar and al report the therapeutic effects of a novel withaferin-A analog, called IMS-088, in transgenic mice expressing hTDP-43 mutants Withaferin-A, a compound extracted from the medicinal plant Withania somnifera has emerged with a therapeutic potential as inhibitor of NF-κB signalling pathway and as inducer of autophagy. Withaferin-A treatment conferred protection in two mouse models of ALS. Withanolides are a group of at least 300 naturally occurring steroids . They occur as secondary metabolites primarily in genera of the Nightshade family. It remains unknown to what end withanolides are produced; they may act as a deterrent for feeding insect larvae and other herbivores.

Despite beneficial properties of withaferin-A, this compound can induce cell death at high dose or prolonged treatment. Addition of methoxy group to withaferin A significantly reduced toxic properties.

The IMS-088 compound obtained from IMSTAR therapeutics is basically the 4-O- methyl withaferin-A which is better tolerated at high doses than withaferin-A in mice. A pharmacokinetic study with 14 C-labeled-IMS-088 revealed that this novel analog penetrates the blood brain barrier after oral intake

The present study shows that oral administration of IMS-088 for 8 weeks in transgenic mouse models with TDP-43 proteinopathy led to reduction of cytoplasmic TDP-43 aggregates in the brain and spinal cord The IMS-088 treatment increased the levels of Beclin-1 and LC3BII which are autophagic markers Of particular interest was the finding that IMS-088 rescued the translational repression of Neurofilament proteins in the brain of the mice expressing mutant hTDP-43 Treatment of mice expressing mutant hTDP-43 with IMS-088, an inhibitor of NF-κB activity, led to reduction of microgliosis and astrogliosis. NF-κB is a transcription factor playing a key role in inflammatory responses including genes encoding cytokines and chemokines. Microglia-specific inhibition of NF-κB pathway has also shown to attenuate neuroinflammation and extended survival by several weeks in the SOD1 G93A mice. From these results, the scientists conclude that clearance of cytoplasmic TDP-43 by IMS-088 in the mouse models is likely the result of a boost of autophagic activity

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

ALS, hypermetabolism and diet

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Patients with amyotrophic lateral sclerosis (ALS) experience progressive limb weakness, muscle atrophy, and dysphagia, making them vulnerable to insufficient energy intake. Half of ALS patients suffer from hyper-metabolism.

In 2014 Edward J Kasarskis and his colleagues developed equations to estimate energy requirements of ALS patients.

They enrolled 80 ALS participants at varying stages of their illness, then developed statistical models to estimate TDEE by using factors easily obtained during a routine clinical visit.

Their predictive equations can serve as a basis for recommending placement of a feeding gastrostomy in ALS patients who fail to meet their energy requirements by oral intake.

They developed a Web-based calculator, but it seems to not work anymore.

I tried to replicate this calculator.

Masitinib is a veterinary medicine used to treat certain cancers in animals. It is also being tested for other neurodegenerative diseases, including amyotrophic lateral sclerosis and progressive multiple sclerosis. However, its effectiveness in ALS remains to be proven.

Masitinib has achieved its main objective in a trial on Alzheimer's disease, according to the main data announced on December 16 by its sponsor, the Parisian company AB Science.

In the six-month phase 2b / 3 study involving 718 patients with Alzheimer's disease, the drug, on average, appeared to stop cognitive decline, but did not show improvement. Fewer patients have progressed to severe dementia. This confirms the results of a previous small phase 2 trial of 34 patients with Alzheimer's disease, where Masitinib stabilized cognition over six months.

While these results are encouraging, it is only so because no other drug seems to work in mild to moderate Alzheimer's disease.

AB Science started the current study in 2013 in Spain, Romania, Poland, Ukraine, Bulgaria and Greece.

Participants were on average 72 years old; about half had mild Alzheimer's disease, defined as an MMSE of 21–25, and the remainder of moderate, defined as an MMSE of 12–20.

The trial included three treatment arms: 3 mg/kg, 4.5mg/kg, and a high dose arm, 4.5mg to 6mg/kg, which had its own placebo control group.

Recruitment was slow, however, leading researchers to abandon the 3 mg / kg arm to focus on the higher doses.

The study design is unusual, it is standard in trials for mild to moderate Alzheimer's disease to require that the two primary endpoints meet the statistical cutoff. Criticism of the study design is not new for Masitinib, but it is likely the result of a group that is financially constrained and trying to move forward as quickly as possible.

The 4.5 mg / kg arm ended up with 182 participants on medication and 176 on placebo. The placebo group decreased slightly on ADAS-Cog over 24 weeks, while the treatment group improved by 1.5 points.

On the main measure, ADCS-ADL, the placebo group decreased slightly and the treatment group improved slightly. On secondary measures, the treatment group had a better trend. Treated participants were less likely to progress to severe dementia, with only 1 percent doing so, compared to 6 percent of controls.

In the high dose arm, the results were not significant. The 186-person treatment group and, oddly enough, the 91-person control group improved slightly on ADAS-Cog and ADCS-ADL. There were more than twice as many serious adverse events in the treatment group: 13% versus 5% in the control groups. These side effects did not follow any obvious pattern, being dispersed among different organ systems.

There are still questions about the mechanism of action. An anticancer drug (kinase inhibitor) having an effect on Alzheimer's disease is quite unique.

AB Science researchers believe that Masitinib may work in several ways to help the brain with Alzheimer's disease. Glial cells have received little attention in Alzheimer's disease research. Finally, Masitinib inhibits the protein kinase Fyn, which has been linked to amyloid and tau pathology, suggesting that the drug may affect these processes. Fyn is associated with T cell and neuronal signaling in development and normal cell physiology. Perturbations in Fyn often have implications in the formation of various cancers.

Company representatives have said they will begin a Phase 3 AD confirmatory trial next year.

In the next phase 3 trial, researchers will use the results of biomarker tests to examine the effects of treatment on different brain conditions. They will only test the 4.5 mg / kg dose and include more AD at an early stage. The company will also continue to develop the drug for multiple sclerosis and amyotrophic lateral sclerosis.

Axons injured in the central nervous system of adult mammals generally cannot regenerate over long distances, which limits functional recovery after central nervous system injury, but also the hopes of recovery in ALS patients. enter image description here Source: Can injured adult CNS axons regenerate by recapitulating development? Brett J. Hilton, Frank Bradke

The potential mechanisms underlying regeneration failure in the mature central nervous system include factors intrinsic and extrinsic to the central nervous system.

The presence of extrinsic growth repellent factors is associated with certain molecules in the extracellular matrix, myelin debris or fibrous tissue, and the limited availability of suitable growth factors.

Strategies to neutralize or attenuate the major extrinsic inhibitors of axonal growth have limited effects on regeneration.

Suppression of PTEN, an intrinsic suppressor of axonal growth, induces appreciable axonal regeneration, and when this suppression is combined with other factors, it allows a significant percentage of retinal ganglion cells to regrow their axons along their entire length. optic nerve.

PTEN is associated with cancer, non-cancerous neoplasms, brain function, autism, and cell regeneration. The strong link of PTEN with inhibition of cell growth is being investigated as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have been shown to enable nerve regeneration in mice.

Nevertheless, more work is needed to identify the main regulators of axon regeneration in the central nervous system. Unlike their central nervous system counterparts, sensory and motor neurons of the peripheral nervous system, they spontaneously display potent growth in response to peripheral axonal injury, which is accompanied by the activation of key genes associated with regeneration (RAG ).

Scientists predicted that the expression of this RAG network would be controlled by a central group transcription factor during the regeneration of peripheral nerves. Indeed, the manipulation of transcription factors at the heart of this network, such as STAT, members of the KLF and Sox family, leads to the growth of axons of the central nervous system.

The scientists then used a System Biology type approach. Enter image description here Systems biology is generally defined in opposition to the traditional so-called reductionist paradigm. The reductionist approach has succeeded in identifying most of the biological components and many interactions but, unfortunately, offers no convincing concept or method for understanding how the properties of the system emerge. Pluralism of causes and effects in biological networks is best addressed by observing, through quantitative measurements, several components simultaneously and by rigorous integration of data with mathematical models (Sauer et al.).

Here, those scientists integrated several existing and newly generated datasets to characterize hierarchical interactions of transcription factors in order to identify regulators that would be potentially associated with axon regeneration.

By comparing gene expression in conditions such as damage to the central nervous system, with behavior in the peripheral nervous system or even in the central nervous system when it has been subjected to powerful pro-regenerative treatments, the scientists emitted the 'hypothesis that they could identify the main transcription factors regulating intrinsic regeneration programs.

The authors began with a network analysis approach based on mutual information to characterize the transcriptional regulatory network formed by transcription factors associated with regeneration in several independent data sets.

They identified a basic three-level subnet of five interconnected transcription factors, composed of Jun, STAT, Sox, SMAD, and ATF, which is remarkably preserved in several models of peripheral nervous system injury and at different time scales. .

Remarkably, scientists have observed a similar, multi-layered and highly interconnected transcription factor structure in central nervous system neurons after genetic and pharmacological treatments that enhance regeneration.

However, in the central nervous system, subnet associated with regeneration and its higher level hierarchical structure have a less interconnected and less hierarchical structure.

Their analyzes identified the RE1-silencing transcription factor (REST), a widely studied regulator of neural development and expression of specific neuronal genes, as playing a potentially important role in suppressing regeneration of the central nervous system. Yet REST expression is strongly correlated with increased longevity. REST levels are highest in the brains of people who have lived to be 90 to 100 years old and who have remained cognitively intact. It is believed that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces expression of stress response genes.

Bioinformatics analyzes have shown that REST is present at the top of a degenerate transcription factor network in the central nervous system, but absent in the peripheral nervous system and in neurons of the central nervous system with improved regenerative potential, both in the optic nerve and spinal cord.

Their findings suggest that REST acts as a potential upstream transcriptional repressor, limiting the interactions of basic regenerative transcription factors to drive RAG expression and the intrinsic growth capacity of central nervous system neurons.

This hypothesis was supported by the transcriptomic analysis of REST-depleted central nervous system-injured neurons which exhibited enhanced expression of a network of regeneration-associated genes driven by several basic transcription factors known to promote regeneration.

To further validate their bioinformatics predictions, the scientists investigated the effects of REST neutralization on regeneration in two different models of central nervous system injury: in vivo optic nerve crush and complete spinal cord injury. In both cases, the neutralization of REST resulted in increased regeneration.

These results demonstrate how a multistage biological systems analysis coupled with substantial experimental validation in vitro and in vivo provides a framework for the discovery of central nervous system repair drivers and implicate REST as a novel regulator of regeneration of axons of the central nervous system.

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

According to most biology textbooks, the main organizing principle of the cell is the membrane. Lipid bilayers envelop organelles, including the nucleus, mitochondria, and endoplasmic reticulum, to keep some proteins inside and others outside.

The rest of a cell's internal machinery is described as floating in the cytoplasm, with proteins sometimes clashing with binding partners, substrates, and small molecule drugs.

Many scientists suddenly realized that their favorite proteins were undergoing biologically relevant phase transitions and they hadn't even realized it.

Biomolecular condensates are aggregates of membraneless molecules, such as proteins and nucleic acids, that organize themselves dynamically to perform a wide range of cellular functions.

There is a growing appreciation for the importance of biomolecular condensates and this is forcing cell biologists to rethink the classical model of the cell.

There are many examples of molecular aggregates. For example glycogen granules in liver and muscle cells, lipid droplets in fat cells, pigment granules in some skin and hair cells and crystals of various types. These structures were first observed by O. F. Müller in 1786.

Research over the past decade has shown that disturbances in condensate behavior play a causal role in a myriad of human diseases.

In amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1, a strong body of literature indicates a causal role in the deregulation of biomolecular condensates.

From the start, it seemed possible that these transient droplets could serve as cellular reaction vessels: speeding up reactions by concentrating the reactants or slowing them down by separating the reactants. More recently, researchers have unraveled their biological role in both health and disease.

In 2012, Michael Rosen, explored the biophysical properties of biomolecular condensates.

The association with the disease began to crystallize shortly thereafter. Paul Taylor, a neurologist at St. Jude Children's Research Hospital, was working to understand the genetics of neurodegenerative diseases and reported in 2013 in Nature that conserved mutations in HNRNPA2B1 and HNRNPA1 were associated with amyotrophic lateral sclerosis (ALS).

In 2015, a complete renaissance was underway. In that year, five papers independently demonstrated that biomolecular condensates were crucial for the phase transitions of biomolecular condensates.

Because biomolecular condensates are prevalent throughout the proteome, these findings have captured the imaginations of cell biologists around the world.

Research on the importance of phase transitions in ALS, in particular, has taken off. Hyman, co-founder of Dewpoint, reported with colleagues that FUS forms membrane-less organelles at sites of DNA damage and in the cytoplasm during stress, and that mutations in FUS that are linked to ALS lead to to aberrant phase transitions.

It appears that ALS-related mutations that affect the dynamics of membrane-less organelle formation make some of these structures more persistent than they would naturally be. Taylor estimates that disturbances in phase transitions account for over 90% of ALS cases.

Other neurodegenerative diseases could also be linked to liquid-liquid phase separation. In 2017, Ankur Jain and Ron Vale proposed that a large set of repeated expansion disorders - including Huntington's disease and muscular dystrophy as well as ALS - could involve the formation of aberrant RNA droplets.

In 2018, Taylor and his colleagues reported that soluble tau species, one of the main culprits of Alzheimer's disease, can form condensate.

Cancer also appears to involve the biology of organelles without a membrane.

“Condensate biology is the kind of science that will rewrite textbooks - and, we believe, rewrite medicine,” said Cary Pfeffer, M.D., acting CEO of Faze and partner at Third Rock Ventures.

Faze Medicines is founded by renowned scientific leaders in the field of biomolecular condensates:

  • Roy Parker, Ph.D., is a pioneer in the study of the class of condensates known as RNP granules with a focus on RNA components and their role in neurodegenerative diseases as well as other diseases.

  • Mike Rosen, Ph.D., is a leading expert in the formation, regulation and functions of biomolecular condensates with an emphasis on the multivalent interactions that are essential to their formation.

  • J. Paul Taylor, M.D., Ph.D., is a pioneer in the field of liquid-liquid phase transitions who made fundamental discoveries defining how mutations that modify these phase transitions impact neurodegenerative diseases.

  • Ron Vale, Ph.D., is a leading expert in molecular motor proteins who recently demonstrated how repeated expansion RNAs can lead to the formation of pathogenic condensates.

Other companies are carefully studying biomolecular condensates.

Not long ago, Nereid Therapeutics was launched with funding of $ 50 million, and Transition Bio debuted with undisclosed seed funding. Dewpoint Therapeutics, a precursor to condensates, has signed agreements with two major pharmaceutical partners since its launch in 2019. Dewpoint and Nereid also work on neurodegenerative conditions, as well as cancer applications.

Faze Medicines focuses on applications in neurodegenerative diseases, but has yet to disclose specific drug targets.

In the short term, all of these companies hope to reverse the harmful biology of condensate. As they learn to control the composition and behavior of condensate, these companies could also tackle new targets.

For example, rather than directly inhibiting a certain harmful molecule, a drug could lock it in a condensate.

Condensates allow us to think about drug discovery in a different way.

The biggest pharmaceutical companies are keeping an eye on this development. Dewpoint has already partnered with Bayer on cardiovascular and gynecological diseases and Merck & Co. on HIV.

Faze Medicines also plans to partner with large companies, says Cary Pfeffer, the company's interim CEO and partner at Third Rock Ventures.

Novartis Venture Fund, Eli Lilly and Company and AbbVie Ventures have all joined the fundraising syndicate, he says, highlighting the interest of large pharmaceutical companies in condensate.

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

AMX0035, some differing opinions.

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On September 3, 2020 we published an article about a new treatment for ALS: AMX0035. This new treatment used a combination of two drugs, including TUDCA which had been advocated for a long time by patients on several Internet forums. The public had also been taken in by the * well publicized * fact that Amylyx is a tiny company. Dr Sabrina Paganoni then stated that the gain due to AMX0035 was modest but significant for the patients.

Several doctors have a different opinion and they expressed it in two letters to the New England Journal of Medicine. In one letter, it appears that the patients recruited into the clinical study also had access to Edaravone, but in different proportions for the control group and the arm group.

The doctor who wrote the first letter claims (and this is quite surprising) that Edaravone harms ALS patients and therefore the control group was penalized. Whatever the influence of Edaravone on the course of ALS, it is still a surprising methodological error and which invalidates the conclusions of the clinical study.

In the other case, up to now the only one answered by those responsible for the clinical trial, a comparison is made with a previous trial and the authors of this second letter to NEMJ affirm that only TUDCA is effective and therefore that the dual therapy proposed by Amylyx has little use. The principal investigators' response is that these are studies with different methodologies and therefore no conclusions can be drawn.

It is still too early to draw any conclusions, but it seems to be a cruel constant in clinical studies on ALS, that their results are always announced as very favorable, and then with experience we realize that in fact the gain is insignificant.

One might wonder why Edaravone's distribution imbalance was introduced. It is only mentioned in the NEMJ article which will probably only be read by a limited number of researchers and not in the protocol published on clinical.gov!

Perhaps this indicates that the confusion of roles (advocated by public authorities) between academic research and entrepreneurship is susceptible to frequent slippages.

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

ALS is a devastating neurological disease, in which the upper and lower motor neurons progressively degenerate, leading to fatal paralysis due to relentless muscular atrophy.

Despite the well-recognized correlation between TDP-43 aggregation and neuronal degeneration, whether this relationship is causal has remained unclear.

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The recent advent of the optoDroplet technique for controlling protein-protein interaction through light illumination has allowed the generation of droplets containing intrinsically disordered proteins in cells with an unprecedented spatiotemporal precision.

Moreover, the use of this optogenetic approach to explore TDP-43 uncovered the neurotoxicity associated with TDP-43 phase transitions in cultured neurons.

In this paper, the authors discuss their recent discovery of novel facets of TDP-43, based on the use of an optogenetic TDP-43 variant (opTDP-43) interrogated in zebrafish motor neurons, in which the in vivo dynamic nuclear-cytoplasmic relocation and the clustering of TDP-43 can be observed directly due to the transparent zebrafish body.

Their results showed that optogenetically clumped optogenetic TDP-43 variant mislocalizes to the cytoplasm and damages motor neurons before the development of large cytoplasmic aggregates, which are similar to those found in the ALS patients.

This unexpected finding raises the possibility that the onset of motor neuron dysfunction caused by TDP-43 in ALS occurs much earlier than previously anticipated; therefore, future efforts should be made to identify the cellular environments and insults that facilitate pathological TDP-43 oligomer formation to better understand, and potentially intervene in, the prodromal phase of ALS and other TDP-43 proteinopathies.

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

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