About obsolete knowledge in ALS scientific literature

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The level of interest and knowledge among scientists about human physiology and anatomy is appalling.

We know that higher primates (including humans) have a special corticospinal system for dealing with tasks that need high skills. Most animal models of ALS do not have this kind of corticospinal system. Another feature of this corticospinal system in higher primates is that the connection from upper motor neurons to lower motor neurons is done directly in some cases (for example the hands), while in most animals the interconnection is done with interneurons, which take in charge automatic and repetitive movements such as walking.

Yet publications are still written that discuss at length of interneurons' role in ALS. One such publication (a review) is interesting as it starts well, by stating the obvious, that as there were hundreds of unsuccessful clinical trials on ALS drugs, we must have missed something important. enter image description here Alas, the authors resort to an old hypothesis, one of the first about ALS etiology, which is the excitotoxicity hypothesis.

This old hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. As the authors recall many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not one was effective.

On the contrary, the authors never mentioned that the only clinical trials that were successful were about mutations in some rare cases (SOD1). A few other clinical trials did better than the average but they were far from providing a cure, they addressed cellular stress. It seems obvious now that for the majority of ALS patients, the cellular stress response is defective.

The authors correctly state that the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays the scientists use to study it.

The authors ask for more research:

  1. Network activity: Assess the activity level of the affected networks, not just excitability.

  2. Individual neurons: Investigate how ALS pathology affects the function of individual neurons, including lower motor neurons and interneurons.

  3. Interneurons: Understand their role and how their activity changes in ALS.

Point 1. looks like we are still in the 1940' with the Nernst and Goldman equations.

Point 2. is about the function of individual neurons. That's weird, people are not made of individual neurons, neuron types are numerous and are not even the sole cell population, and there are many more non-neuronal cells than neurons in the CNS. All these cells type collaborate and compete in what we call "tissue".

Point 3. is weird, ALS strikes a special kind of muscle (skeletal muscles) and nerves (corticospinal). In most cases, the lower motor neurons that connect to these muscles are not themself connected to an interneuron.

What to conclude from this review? I assume the authors are in good faith, but by perpetrating obsolete ideas they slow any progress toward a cure for ALS

The corticospinal system and ALS

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Here is a summary of an educational article that will be of particular interest to people affected by ALS (Lou Gehrig in the USA/Charcot's disease in France).

Essentially the article explains that ALS is a disease specific to certain nerve formations that are absent in most mammals, except certain higher primates (and perhaps other mammals like the Degu). These formations being absent in rats and mice, we wonder what the purpose of preclinical trials on these rodents is. I think this is the main contribution of the article.

There are indeed key differences in the organization and function of the corticospinal system in primates compared to non-primates, such as rodents. enter image description here Cortico-motoneuronal projection is a late evolutionary development that is present only in dexterous primates, such as capuchins, macaques, great apes, and humans, but absent in adult rodents, carnivores, and many others. primates, such as marmosets.

Although tool use is not exclusive to advanced primates and humans with demonstrable cortico-motoneuronal connections, primates exhibit a wide range of tool-making and use behaviors. Why did the direct projection from the cortex to the α motor neuron appear so late in evolution? One possibility is that the cortico-motoneuronal system acts selectively on the motor apparatus of the upper limb to allow relatively independent finger movements. These movements are essential for performing all skilled manual tasks, including key human motor characteristics, such as gestures and tool use.

Corticospinal neurons located in the motor areas of the cerebral neocortex project axons onto the spinal network. The corticospinal system of primates has a wider cortical origin than in other animals and a wide range of fiber diameters, including thick, rapidly conducting axons. Direct cortico-motoneuronal projections from the motor cortex to motor neurons of the arm and hand are a recent evolutionary feature, well developed in dexterous primates and particularly in humans. This system is involved in the control of skilled movements, performed with the splitting of the distal extremities and at low levels of force. During movement, corticospinal neurons are activated in a very different way from “lower” motor neurons, and there is no simple or fixed functional relationship between a so-called “upper” motor neuron and its target lower motor neuron, whereas in other mammals there is an interneuron which makes the junction between an upper motor neuron and a lower motor neuron.

During the development of ALS, there is a selective loss of rapidly conducting corticospinal axons and their synaptic connections, which is reflected in responses to noninvasive cortical stimuli and measures of corticomuscular coherence.

A given muscle can be used in different ways, and one of the key features of the cortico-motoneuronal system is the recruitment of particular, task-specific muscle groups. There is task-specific flexibility between the activity of a cortico-motoneuron and its target motoneurons. This is lost when the cortico-motoneuronal projection is dysfunctional and, as would be expected, there will then be deficits in skill as well as muscle strength.

The well-known weakness and loss of motor units in the hand muscles of ALS patients is more pronounced in the thenar (thumb) muscles than in the hypothenar (little finger) muscles. Although several different factors are known to contribute to lower motor neuron (spinal) dysfunction, these particular changes are due to the greater loss of the cortico-motoneuronal system on the thumb muscles compared to the little finger muscles.

This particular vulnerability of muscle groups heavily used during ALS is not limited to the hand. This includes studies on “split elbow,” “split foot,” and “split ankle.” In all three syndromes, the most profound weakness was seen in muscle groups that, in healthy controls, are known to receive relatively strong cortico-motoneuronal projections.

Along with the corticospinal projection from the cortex to the spinal cord, there is a significant corticobulbar projection to the motor centers of the brainstem, which is essential for actions such as speaking, chewing, and swallowing.

It is important to clarify that the corticospinal system is multifunctional and concerns not only movement but it also has somatosensory, autonomic, and trophic functions. When preparing for and executing the movement, it does not work in isolation, but in concert with other motor systems in the brainstem and spine.

In conclusion, because in rodents, corticospinal projections from the sensorimotor cortex primarily avoid the ventral horn and have limited direct effects on motor control, the pyramidal neurons giving rise to these projections are not considered similar "higher motor neurons." to those of primates, it is therefore not a good model for studying the effects of potential drugs on ALS. A small number of carefully designed studies in higher primates remain needed to advance the understanding and treatment of ALS.

Targeting 14-3-3θ-mediated TDP-43 pathology in mice

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Every day brings its share of scientific articles announcing the imminent arrival of drugs for neurodegenerative diseases.

However, we are unable even to diagnose these diseases with certainty. The diagnosis is made by exclusion and sometimes gives rise to several different diagnoses. We would be better off talking about the spectrum of neurogenerative diseases. The only thing we know for certain is that these diseases are characterized by malformed protein aggregates in inappropriate places in cells.

These diseases are currently differentiated by scientists by the type of protein involved, but in fact, all of these malformed proteins are present to varying degrees in all of these diseases. The recent trend to generalize diagnosis based on molecular markers only recognizes our incompetence and only serves the pharmaceutical industry.

Amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) are most often characterized by the cytoplasmic deposition of nuclear TAR-binding protein 43 (TDP-43). But this is rarely of a rare and deleterious protein form. Although the cytoplasmic localization of TDP-43 aggregates is commonly associated with ALS/FTD, it is unknown what causes the dysfunction, although different hypotheses have been posed such as cellular stress, for example (but not only) due to to a significant change in metabolism.

In a recent article, scientists from Macquarie University in Australia reported their work concerning the interaction between the proteins 14-3-3θ and TDP-43, which regulates the nuclear-cytoplasmic shuttle.

The 14-3-3θ protein, like many other proteins, is associated with several neurodegenerative diseases.

Similar work was carried out in the past (2016) which consisted of creating a peptide by attaching the M1 section of TDP-43 to a TAT peptide which gives a peptide: YGRKKRRQRRRAQFPGACGL, which repatriates the aggregates poorly localized in the nucleus of the cells.

This work does not seem to have given rise to recent developments in the field of neurodegenerative diseases. In any case, this 2016 work did not explain why these aggregates appeared. They only provided a mechanism to get them back into the cell's nucleus. It is not clear how this would have formed them correctly since this happens in a cellular organ called "endoplasmic reticulum" which is located in the cytoplasm.

In addition, forming proteins requires energy, but we know that the cells of many patients are in a state of "hibernation" called the cellular stress response, with activity reduced to the minimum necessary to survive. Furthermore, any genetic therapy only "infects" a fraction of cells, which reduces its interest. And these genetic therapies are not without side effects.

This new article presents a slightly different mechanism but does not further answer the questions above. The 14-3-3θ protein belongs to a family of proteins called 14-3-3, known to regulate other proteins by binding to them and they play a role in various cellular processes, including signaling, survival, and cell differentiation. This family includes more than 200 members. The authors found that neuronal levels of 14-3-3θ were increased in mouse models of ALS and sporadic FTD with TDP-43 pathology. As we already know, 14-3-3θ is associated with several neurodegenerative diseases. Scientists believe that the interaction of deleterious TDP-43 alleles with the 14-3-3θ protein results in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, which resembles the pathological changes caused by these diseases in humans. enter image description here What is interesting is that 14-3-3θ seems to interact preferentially with pathogenic TDP-43 versions but not with the usual version of TDP-43. This suggests that reducing the production (or increasing the degradation) of 14-3-3θ would reduce the production of pathogenic TDP-43. Scientists have therefore sought to reduce the amount of this 14-3-3θ protein in cells through genetic therapy.

The authors designed multiple versions of a peptide they called CTx1000, each version of which is tailored to reduce one of these deleterious forms of TDP-43. This reduction is mediated by degron of pathogenic TDP-43. A degron is a part of a protein that plays an important role in regulating protein degradation rates. In mice that underwent this gene therapy, functional deficits and neurodegeneration decreased, including when they were already symptomatic at the time of treatment. This incidentally matches many studies that, contrary to consensus, show that motor neurons do not die in ALS.

The university's press kit is, as usual, dithyrambic and the authors' statements resounding: "This new research is incredibly promising in slowing the progression of MND and FTD for the vast majority of our patients. I'm extremely hopeful that it will soon be available to our patients at the Macquarie University Hospital MND Clinic." This type of press kit is not aimed at patients and their loved ones, but rather at potential investors.

In conclusion, we can think that just as the therapy proposed in 2016 did not allow the development of a drug eight years later, it will probably be the same for this one, because it does not answer basic questions: Quid patients (the majority) who do not present a mutated form of TDP-43? What causes these protein clumps? Where can cells find the energy to be permanently “reactivated” from cellular stress response so that the therapy can do its work? How can we ensure that all of the targeted cells can receive the therapy, without side effects?

This post is about an interesting hypothesis. Hypotheses abound, yet few a convincing.

Half of patients with Alzheimer's disease, Parkinson's disease, or ALS have insulin resistance. Obesity and diabetes have been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). This means the cells of their body cannot let the glucose enter them. Glucose is the main energy source as it is converted into ATP. Glucose is for short-term (day) energy needs. Another source of energy is lipids (fat). Lipids are even more dense than glucose energy-wise.

The body needs an enormous amount of energy. With all the lipids in the body of a healthy person, you could charge two Tesla cars! The brain (a part of the CNS) needs 20% of all energy intake.

A new paper argues that cells shift their metabolism from glucose to lipids under stressors. It tells that one notable distinction between glucose and lipid metabolism is in the quantity of oxygen required to generate each ATP molecule. Lipid metabolism needs two times more oxygen than glucose metabolism. The result is two times more damaging ROS (a by-product of metabolism). enter image description here Studies have shown that oxidative stress and endoplasmic reticulum stress are correlated and can lead to protein misfolding (Abramov et al., 2020). Accumulation of misfolded proteins causes cellular damage and mitochondrial dysfunction and is associated with a range of neurodegenerative diseases, including ALS (misfolded SOD1, TDP-43, C9orf72) (McAlary et al., 2020), Parkinson's disease (misfolded α-synuclein) and Alzheimer disease (misfolded Aβ and Tau) (Abramov et al., 2020).

It explains also the accumulation of iron in patients' brains: To transport oxygen the blood cells need iron, and as the glucose in the blood is not absorbed in cells, it induces a change in microbiota.

It's also well known that SCFAs (including butyrate) have a positive effect on neurodegenerative diseases by their action on microbiota. SCFAs help to restore glucose as the preferred energy substrate. Authors say there are other means to restore glucose as the main source of energy.

What to think about this paper? First, some authors belong to a biotech so we can expect they want to promote their drug: Mitometin. Second, this is a review, this is not even a pre-clinical study, yet some of the authors were involved in pre-clinical studies on this topic. Other groups have written on this topic. What to make of this? Acetyl-CoA carboxylase might be of interest as they produce malonyl-CoA which inhibits the CPT1 gene that regulates lipid metabolism. B7 vitamin is known to convert acetyl-CoA to malonyl-CoA for fatty acid synthesis.

Expression of C9orf72 regulates IL-17A signaling in mice blood

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No one knows how to define what ALS is, its diagnosis is made by exclusion. Efforts are underway to define ALS based on molecular markers, but clearly, this would primarily be in the interest of the pharmaceutical industry.

If we do not know how to define what constitutes ALS rather than, for example, extreme cases of myasthenia gravis, it is difficult to find the cause(s).

The hypothesis of infection or poisoning is old, but apart from the case of BMAA, a neurotoxin produced by a cyanobacterium, this type of hypothesis has never been confirmed.

A peripheral hypothesis to that of infection is that of inflammation, either intraCNS or resulting from infiltration across the blood-brain barrier. There are countless studies on this subject but none are compelling.

What exactly does “inflammation” mean? Human immune systems are among the most complex systems in terms of physiology. To summarize, there are two strictly separated areas in our body: The central nervous system and the rest of the body. The CNS immune system is poorly understood. In the rest of the body, we could say that there are two kinds of subsystems, the innate nervous system which is the only one to protect us from our birth until the development of the acquired immune system. It is also the only one to protect us when the acquired immune system atrophies from the age of fifty. But these two systems interfere and the separation is only clear in medical textbooks.

Between these two systems, there is a sort of messaging system comprising many molecules with varied roles, including the famous cytokines.

One of them is called Interleukin-17A (IL-17A). A few studies have linked it to ALS since 2010, but hundreds of molecules have been associated with ALS. enter image description here The paper we are discussing today, like most of them, does not present a major discovery, but it has some interest.

The scientists used a mouse model with a mutation in the C9orf72 ORF that impairs blood cell production. We are far from ALS, except for the C9orf72 ORF which is associated with the majority of cases of familial ALS.

They found, among other things, that this C9orf72 mutation interacts with the immune system by increasing the production of IL-17A and CD80, which is associated with autoimmune diseases such as psoriasis or multiple sclerosis.

Using an IL-17A antibody they were able to improve the condition of the mice. But usually, scientists use hyperboles very extensively. For example, one of the authors does not hesitate to say; "Our research indicates that IL-17A blockade may be quickly repurposed to treat ALS patients to slow down the progression of their disease or possibly stop ALS from ever occurring."

It's very unlikely, but who knows?

What seems surprising about this study and these claims is that the impact is not studied on the CNS immune system. The reasoning is done by analogy ("Patients with C9ORF72-related ALS similarly showed CD80 enrichment in spinal cord microglia."). Reasoning by analogy, although common in scientific publications, should be banned, you can "prove" anything this way.

Activated CD8+ T cells may mediate neuropathology during viral infection

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Scientists are never short of new hypotheses about the cause and even the nature of diseases. For example, some of them now believe that “inflammation” is the underlying cause of many neurodegenerative diseases.

The human immune system is made up of different subsets of extreme complexity. The main mode of action is quite brutal, as the cells renew themselves quite quickly (from a few days to a few weeks), any slightly suspicious cell is deliberately killed by one of the agents of the immune system.

The central nervous system is composed of cells that have a probable lifespan of a hundred years or more, and they do not renew themselves through division, so this mode of operation is impossible. Therefore the central nervous system is kept isolated from the rest of the body through the blood-brain barrier and it has its own immune system.

Breaks in this barrier and the invasion of the CNS by the body's immune cells have sometimes been suggested as being able to cause diseases such as ALS, and now Alzheimer's. enter image description here A new article aims to show that in the case of Zika viruses, the terrible consequences that an infection causes are not due to the infection of cells by the virus, but by the invasion of the CNS by immune cells from the rest of the body.

The article incriminates CD8+ T cells which function like NK cells, formidable killers.

Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis.

Of course, this article is based on an experiment with mouse models of a disease, so it is quite risky to draw conclusions for humans.

In any case, once the damage is done, it is too late, as the neurons do not reproduce. Yet it is possible to have a form of damage mitigation, either thanks to neurogenesis in certain rare cases, or even to a sort of mutual aid mechanism between neurons, which causes a surviving neuron to try to take over the work of the dead neurons. This is what causes us to become clumsy as we age.

Therapy is therefore not to be expected quickly, the best is to maintain a healthy blood-brain barrier, that is to say, to follow the precautions recommended for cardiovascular diseases.

Open innovation challenge

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Now you have an opportunity to fast-track the discovery of drugs in some neuro-degenerative diseases.

AstraZeneca, the pharmaceutical company, proposes a challenge in the area of nucleotide repeat expansion disorders, which includes ALS (Charcot/Gehrig) disease, but also Huntington's disease, etc...

Typically you have to be a startup or an academic with a plan to launch a startup because your solution must be translated into practice within a 12–18-month timeframe.

I am willing to provide reasonable help if you hesitate. This will be mostly in terms of shaping your proposal. I believe that AstraZeneca, like other large companies, is not interested in unproven, hypothetical ideas. On the contrary, IMO they search for people with energy and time (and intellectual right) to give blood to ideas where there is a consensus but where nobody cared to develop it in the pre-clinical stage.

I guess also AstraZeneca would prefer a simple implementation, instead of a complex one. So for example, a small molecule proposal would be preferred to a genetic therapy. A compound of two or three existing drugs to an untested drug. You get the idea.

Good luck!

Jean-Pierre Le Rouzic You will find the link to email me at the bottom of this page.

ALS: A new therapy from China?

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An article on SCMP tells about an observational clinical trial on six patients testing a new gene therapy: SNUG01.

It's about a genetic therapy proposed by a Chinese company: Sineugene.

This is not even a phase I clinical trial, what is known at the present state is that pre-clinical studies were promising (as usual) and it seems to have beneficial effects on one patient. If this is confirmed in larger trials, it would be a first: No ALS therapy has been able to reverse a bit of the disease. Please understand that the patient just slightly improved, it's not a cure.

Similar assertions have been made in the past by Western companies, sometimes going to the point of ridicule, like claiming patients were able again to do gym and motocross, even while the FDA rebuked the drug. I trust the FDA, not those companies. Yichang Jia, Ph.D. Yichang Jia, Ph.D., Co-founder of SineuGene

There are few scientific publications on this new therapy, here is what I understand: The underlying thesis of the scientists is that ALS (or FTD, PD and even Alzheimer(s disease) happens when there are both: * A genetic variant of some gene (which generates RNA-binding proteins (RBPs)) * A cellular stress (it could be a lot of things including insulin resistance) When those two conditions are met, stress granules which are normal phenomena are not processed correctly, instead in disease-susceptible neurons, stress induces mislocalization of mutant RBPs into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology.

It's not known how SNUG01 (there are other names) works, here are some guesses: As the problem stems from the concomitance of two events, removing one of them could (partially?) solve the problem. We know that Relvyrio, TUDCA, and other drugs try to relieve cellular stress. But they are not very efficacious. One possibility as SNUG01 is a gene therapy, it that it tries to remedy the genetic variant. Hence the large therapeutic target that is announced.

I guess that it would be a knock-in therapy, contrary to the knock-out and ASO technologies that are favored by Western scientists. Or it could combine both: Deleting the wrong sequence and inserting a new correct one. Yet it is an AAV gene therapy so the payload can't be large, and a sophisticated gene therapy is unlikely.

AAV gene therapies have some problems and side effects, let's hope they are solved. One main problem is that there are millions of target cells to infect and trillions that should not be infected. Current gene therapies are unable to reach both goals.

The paper we discuss today focuses on the role of dipeptide repeats, particularly poly(proline-arginine), generated from GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are involved in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in carriers of certain C9orf72 gene variants.

The study indicates that the evolution of cells carrying certain sequence repeats of the C9orf72 gene (called PR20), is influenced by the distribution of these sequences in the nucleus. But the important point from the point of view of patients and caregivers is that these sequences can be hindered by a nuclear import inhibitor called importazole. As importazole can block the nuclear import of PR20, it suggests that the nuclear localization of PR20 is crucial for its cytotoxic effects. Yet importazole is not a clinically approved drug, the use of importazole is mainly confined to laboratory research to understand cellular functions that involve nuclear transport. enter image description here In their search for drugs, the scientists investigated BRD4 inhibitors, such as JQ-1 and I-BET762, which restrict the cytoplasmic localization of the PR20 dipeptide of the C9orf72 gene, and thus diminish its cytotoxic effects. BRD4 is involved in the regulation of transcription and the transmission of epigenetic information during cell division.

In 2016, BRD4 was found to possess histone acetyltransferase activity. Histones are essential components of chromatin and play a crucial role in gene regulation. They act like spools around which DNA winds to create structural units called nucleosomes. The nucleosomes are in turn enveloped in very compact chromatin. Histones also protect DNA against possible damage.

The ability of histone acetyltransferases to manipulate chromatin structure makes them essential for cell maintenance and survival, but they have also been implicated in the progression of neurodegenerative diseases.

Inhibition of BRD4 results in increased expression of histones, causing their accumulation in the cytoplasm. These cytoplasmic histones limit the distribution in the nucleus of the PR20 dipeptide derived from the C9orf72 gene.

I-BET762 is a bromodomain and extraterminal (BET) inhibitor. BET inhibitors specifically target bromodomains, which interact with histone proteins. JQ1 is a thienotriazolodiazepine and another potent inhibitor of the BET family of bromodomain proteins.

Interestingly, the introduction of histones alone is sufficient to protect the cells of the dipeptide derived from repeat sequences from cell death induced by the C9orf72 gene.

Phenylephrine, a drug used to treat nasal congestion, also induces cellular hypertrophy and cytoplasmic distribution of histones, providing additional protection against the PR20 dipeptide of the C9orf72 gene.

The researchers propose that temporary induction of the presence of cytoplasmic histones may attenuate the neurotoxic effects of dipeptide repeat proteins.

A problem is that some BRD4 inhibitors have a short half-life in the body, which would require almost continuous administration. On the other hand, phenylephrine is a medication commonly used as a decongestant, but cannot be used by people with hypertension.

Muscle wasting mediated by glucocorticoid signaling in mice

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As a layperson I have been studying ALS by reading scientific publications for several years, it started after the second time someone went ill in my family. This blog is the result of that effort. Scientists claim to find cures for most chronic diseases every week by targeting one or the other obscure molecule. We know that most of these articles are of very poor quality. What feels important to me are articles that show a good knowledge of human anatomy and physiology. I don't care about molecules in mice.

Nearly one century ago, medical doctors made a parallel between spinal cord injury and spinal-onset ALS. In both cases, there is important muscle wasting. And this is what kills people, so it's important to understand how this develops and what are the consequences. enter image description here Obviously, a spinal cord injury will sever the link between the brain motor area, some upper motor neurons, and corresponding lower motor neurons and muscles. Yet it does not stop there, which is particularly interesting when we have ALS in mind. In spinal-onset ALS the disease starts in a very localized muscular for example a muscle in the thumb, and it spreads, often until respiratory muscles fail.

Similarly, a spinal cord injury has consequences that are far from being limited to some motor neurons and diseases. For example, pulmonary infection is a leading cause of morbidity after spinal cord injury. Bizarrely this happens because spinal cord injury causes atrophy and dysfunction in the lymphatic system, an organ system in vertebrates that is part of the immune system.

Now scientists from Ohio, describe systemic wasting that affects innervated non-paralyzed skeletal muscles. The muscles that are affected in ALS are also skeletal muscles. This wasting appeared within 1 week after experimental spinal cord injury in mice and in three weeks half of the muscle mass disappeared. This waste affects the whole body. Skeletal muscle fibers are broadly classified as "slow-twitch" (type 1) and "fast-twitch" (type 2). This muscle wasting affects fast type 2 muscles preferentially, and became exacerbated after a third thoracic vertebra (T3) paraplegia compared with low (T9) thoracic paraplegia. The T3 vertebra is situated at the level of the shoulder, while the T9 is at the height of the sternum.

Markus E. Harrigan, Jan M. Schwab et al. remark that the wasting of nonparalyzed muscle and its rapid onset and severity cannot be explained by disuse, so it implies unknown systemic drivers. Mechanisms underlying systemic muscle wasting (including fully innervated non-paralyzed muscles) early after paraplegic SCI would imply the presence of biological signaling which can quickly reach muscles of the entire body. Knowing the cause of this widespread muscle wasting after a T3 paraplegia in spinal cord injury might illuminate the similar phenomena in ALS.

The authors found that muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature early after T3 spinal cord injury. They generated an inducible skeletal muscle-specific glucocorticoid receptor (GR) knockout mouse model in order to test that hypothesis.

Spinal cord injury-induced systemic muscle wasting was mitigated by (i) endogenous glucocorticoid ablation (adrenalectomy) and (ii) pharmacological glucocorticoid receptor (GR) blockade and was (iii) completely prevented after T3 relative to T9 spinal cord injury by genetic muscle-specific GR deletion.

These results suggest that hypercortisolism contributes to a rapid systemic and functionally relevant muscle wasting syndrome early after paraplegic spinal cord injury in mice. Indeed in humans, hypercortisolism induces central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Hypercortisolism has also been implicated in ALS, maybe it would be interesting to test glucocorticoid inhibitors in a clinical trial. There are studies (here or here) that show that glucocorticoid inhibitors ameliorated the health in an ALS mice model.

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