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It’s unknown why misfolded aggregates appear in cells cytosol during neurodegenerative diseases. If the forming mechanism was elucidated it would enable designing new and efficient therapies. One of those protein aggregates is composed of misfolded TDP-43. Aggregates hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43 are found in frontotemporal dementia, in amyotrophic lateral sclerosis and in some cases of Alzheimer and Parkinson.

My feeling is that scientists, from Academy of Scientific and Innovative Research (AcSIR) in India, achieved one of the most important milestone since 2006, when Virginia Lee provided evidence of involvement of TDP-43 in ALS.

For the proper functioning of the cells, neutral pH is required. However during normal metabolism, all foods create waste products which are acidic. Accumulated waste and toxins ages the cell, sometimes causes it to change to a sick or abnormal cell. For example the cytosol of yeast cells acidifies during aging.

Cells experience a variety of stress-like conditions, in particular, nutrient starvation stress acidifies the cytosol and increases the cytosolic proton ion concentration due to the reduced efficiency of ATP proton pump.

In chemistry, protonation describes the addition of a proton to a molecule, forming an acid. Some proteins or protein domains inside the cells can function as biosensors. It has been proposed that cells sense starvation stress at the molecular level by protonating the side chains of biosensor protein molecules.

The scientists Divya Patni  and  Santosh Kumar Jha observed in a previous study that one domain of TDP-43 (tRRM) could function as a biosensor and sense pH stress. They shown that under low-pH conditions, mimicking starvation stress, TDP-43tRRM undergoes a conformational change named "L structure". enter image description here The L form structure is held by weak interactions and eventually fully misfolds and oligomerizes to form a β-sheet rich "β form". The unstructured regions of the protein gain structure during L ⇌ β conversion.

TDP-43 consists of 4 domains:

  • An N-terminal domain
  • Two RNA recognition motifs RRM1 and RRM2 working as a tandem (tRMM)
  • An unstructured C-terminal domain.

In this paper, Patni  and  Jha showed that the monomeric N form of TDP-43tRRM forms a misfolded amyloid-like protein assembly, β form, in a pH-dependent manner.

The side chains of the ionizable amino acid residues buried inside the protein structure can protonate or deprotonate only upon partial or complete unfolding.

They are promising candidates to function as gatekeeper residues for protein aggregation as it often begins with partial unfolding of the protein.

The scientists from the Academy of Scientific and Innovative Research in Ghaziabad India, hypothesized that ionization of a protein side-chain buried in the protein structure might be coupled to the formation of the misfolded β form.

An examination of the protein structure revealed that out of all of the amino acid residues whose side chain could titrate in the acidic pH range, only D105, H166, and H256 are almost completely buried in the protein structure. They systematically mutated these residues to neutral amino acids whose side chains cannot undergo protonation-deprotonation reaction ( D105A, H166Q and H256Q).

Patni  and  Jha observed that D105A and H256Q behaved like TDP-43tRRM in their pH-dependent misfolding behavior. However, H166Q retained the N-like secondary structure under low-pH conditions and did not show pH-dependent misfolding to the β form.

These results indicate that H166 is the critical side-chain residue whose protonation triggers the misfolding of TDP-43tRRM.

These results indicate that the protonation of H166 functions as a critical trigger switch that controls the amyloid-like misfolding of TDP-43tRRM upon pH stress sensing. It appears that the protonation of H166 results in proximal or distal conformational changes that initiate the misfolding of the protein.

It’s suspected since a long time that the RNA-Recognition motifs of TDP-43 may play a role in the aberrant self-assembly of the protein. Now a clear mechanism of action had been described, while it may not be the only one, hopefully it will enable the design of new therapies.

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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.

There is growing interest in the possibility that Alzheimer's disease is triggered by infection because the Alzheimer's disease brain signature protein, Aβ peptide, has antimicrobial activity and therefore Alzheimer's disease could be a consequence rather than a cause of Alzheimer's disease. Alzheimer's disease Several observational cohort and case-control studies have shown reduced rates of dementia after certain types of vaccines. Twenty years ago, Verreault and his colleagues reported that vaccine exposure (diphtheria / tetanus, polio, influenza) was associated with a 25-60% reduction in the subsequent development of Alzheimer's disease.

Klinger and colleagues have demonstrated a significantly reduced risk of developing Alzheimer's disease in patients with bladder cancer exposed to repeated intravesical applications of the Bacillus Calmette-Guérin vaccine, particularly in the 75-year-old population. and more.

Scherrer and his colleagues showed a significantly reduced rate of dementia in people vaccinated against tetanus, diphtheria and pertussis and shingles compared to those unvaccinated.

Liu and his colleagues found a reduced rate of dementia in patients with chronic kidney disease vaccinated with the influenza vaccine.

Population-wide observational cohort studies indicate a moderate to no positive association between a diagnosis of human herpes virus infection and incident dementia, and some studies indicate a potential mediating role of antiherpetic drugs.

The varicella-zoster virus (called VZV, for varicella-zoster virus) is a herpesvirus, also called HHV-3 (human herpesvirus 3), which causes chickenpox or shingles.

Human herpes viruses, also known as varicella-zoster virus, are usually contracted in early childhood when they cause chickenpox, but the virus persists throughout life and may recur in older people as shingles, and has also been associated with postherpetic neuralgia, encephalitis and / or meningitis, and respiratory disease.

To reduce the effects of the re-emergence of human herpes viruses in the elderly, national vaccination strategies have been implemented in the UK and elsewhere.

In Wales, a national shingles vaccination has been carried out since 2013, with the aim of vaccinating people aged 70 years, and a catch-up vaccination at 79 years for unvaccinated people at 70 years.

Until 2018, the only shingles vaccine available in Wales was a live attenuated vaccine against the human herpes virus (Zostavax). Since June 2018, a small proportion of the Welsh population has received the recombinant shingles vaccine (Shingrix).

In this new pre-print publication, Christian Schnier, Janet Janbek, Richard Lathe and Jürgen Haas analyzed the association of shingles vaccination with incident dementia in people vaccinated in Wales between 2013 and 2020 in an observational cohort study using national health data collected retrospectively. In addition, they analyzed whether this association was mediated by a reduction in diagnosed shingles and whether the association had a different degree in Alzheimer's disease and vascular dementia.

People exposed to the vaccine had a 39% reduced risk of being diagnosed with dementia after vaccination. This association is close to that published by Scherrer and colleagues who found a 43% reduction in dementia in people vaccinated against shingles.

The reduction in dementia in people exposed to the vaccine was slightly more pronounced for vascular dementia than for Alzheimer's disease. If true, their results suggest an association between shingles vaccination and cerebrovascular disease, rather than an association of vaccination with the pathological accumulation of toxic proteins in the brain such as the beta-amyloid peptide and the protein tau.

However, their results should be interpreted with caution because the total duration of follow-up of those vaccinated and subsequently diagnosed with herpes zoster was low, resulting in wide confidence intervals in the estimate. People exposed to the shingles vaccine had a lower risk of death from all causes except cancer, this finding could indicate a nonspecific effect of the shingles vaccination.

One potential interpretation of their results, therefore, is that the live attenuated varicella-zoster vaccine acts as an adjuvant that plays a role in immune responses against microbes.

This interpretation is supported by: (i) documented cross-immune protection when infection with one pathogen can alleviate disease caused by a second unrelated pathogen, (ii) the fact that an immune adjuvant (alum) has been reported to delay the development of Alzheimer's disease, (iii) the fact that a potent adjuvant vaccine (Bacillus Calmette-Guérin) reduces the rates of Alzheimer's disease in patients with bladder cancer.

These theories of the negative association between varicella zoster virus vaccination and dementia, however, should be considered, alongside other potential theories. Indeed, their results could come from a selection bias. Indeed, non-specific effects of the vaccine, such as lower mortality, have already been described in observational cohort studies of vaccine efficacy by Simonsen and colleagues, who attributed the association to selection bias for fragility .

To control for the selection bias of frailty, scientists at the Universities of Edinburgh and Copenhagen adjusted frailty between 65 and 70 years of age, retirement home residency, and the multiple illnesses that make up the Charlson Co-morbidity Index.

The authors cannot exclude with certainty that unvaccinated people may have a lower healthy life expectancy. This observation would be supported by the results of vaccine efficacy studies for Zostavax, which showed no significant difference in mortality between people exposed to the vaccine and those exposed to a placebo.

In addition, although their study population was large and representative of the Welsh population, the average follow-up period was rather short, as the introduction of the vaccine into a national campaign was made in 2013, which gave maximum follow-up time. about 6 years old (up to the age of 76).

It is well known that approximately 10% cognitively well patients undergoing surgery will develop symptoms of cognitive dysfunction after their procedure but will recover quickly. A few percent of them will develop a Parkinson disease. It is known that persistent degree of cognitive impairment will appear in up to 10% of elderly patients up to three months after a surgical procedure. No large studies had studied the impact of surgery and anesthesia on Alzheimer disease.

There is some relation between Parkinson disease and the digestive system. Aggregated alpha synuclein is a pathologic feature of Parkinson’s disease. It has been found in the gastrointestinal tract early in the onset of the Parkinson’s disease. There has been conflicting reports on whether appendectomies increase the risk of Parkinson’s disease. The overall Relative Risk (RR) of developing Parkinson’s disease in patients after appendectomies is usually estimated at a few percent.

The aim of the current study by Chih-Sung Liang, Mu-Hong Chen of National Yang-Ming University, Taipei, was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis.

The scientists used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years.

Patients developing appendicitis and those receiving appendectomy for appendicitis had higher incidences of Alzheimer disease than the controls during the follow-up period. A Cox regression analysis showed that those patients were more likely to develop Alzheimer disease than the controls.

These patients also had higher risks all types of dementia but not for vascular dementia (which is often associated with aging) than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis.

Alzheimer's disease has a multifactorial etiology. Diet, cardiovascular disease, low grade systemic inflammation have been associated with it. All of these factors have some relationship with the gastrointestinal tract.

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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.

Here is an example of systematic review about an anti-depressant which has also putative benefits in human neurodegenerative diseases.

A systematic review are designed to provide an exhaustive summary of current evidence relevant to a research question. This should not be confused with meta-analysis. A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. A key benefit of this approach is the aggregation of information leading to a higher statistical power. 

However most meta-analysis are cheap attempts at publishing without doing real research. Systematic reviews must follow strict protocols. There is no cheap or easy way to do a systematic review. enter image description here.

Although it is FDA-approved only for use in the treatment of major depression, trazodone is widely used off-label to control agitation and insomnia in Alzheimer’s disease (AD) and other diseases. Yet the list of trazodone side-effects is long and some of them are frightening.

Trazodone hydrochloride and dibenzoylmethane were identified by the National Institute of Neurological Disorders and Stroke (NINDS) small-molecule library screening performed on 1040 drugs. Both drugs reversed p-eIF2α mediated translational attenuation and were neuroprotective in two mouse models of neurodegeneration. In prion-diseased mice, both drugs restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

Furthermore, in an animal model of tauopathy-FTD (frontotemporal dementia), these compounds rescued memory deficits and hippocampal atrophy. Finally, both compounds were not toxic to the pancreas.

A common factor in neurodegenerative diseases, and beyond many chronic diseases is a cellular stress response that is abnormally prolonged. The response to this cellular stress (UPR, ISR and others) involves the shutdown of functions that are essential for the proper functioning of the body.

A cell main purpose is to produce proteins. This production is done in several steps: a blueprint is assembled from RNA fragments copied from DNA (a very long molecule). This blueprint is used by ribosomes to produce linear chains of amino acids. Ribosomes are often located in the rough endoplasmic reticulum, probably the most complex organelle in the cell. The endoplasmic reticulum folds this linear chain of amino-acids, thereby giving it new properties and sends it where it is needed.

When there is a cellular stress response, the endoplasmic reticulum stops working, so the newly produced proteins stay in the cytosol where they form protein aggregates named stress granules. Normally this state is of short duration, so quickly the endoplasmic reticulum works again and the stress granules are disposed by the proteolysis mechanism. In a state of stress response, there is hardly any protein production but the protein consumption resulting from metabolism continues, so if the stress response persists a long time the cells become gradually beyond repair and are destroyed by apoptosis.

A drug able to end the anomalous cellular stress response would therefore be very interesting. Indeed it would be valuable only in early phases of the disease, before too much cells died. And canceling completely the UPR mechanism is a bad idea.

UPR acts as a cellular mechanism for the regulation of protein homeostasis when there are misfolded proteins and coordinates this process through three ER transmembrane proteins: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).

Trazodone acts in the PERK branch of the UPR pathway downstream of eIF2α-P, preventing it from reducing levels of the ternary complex, allowing protein translation to occur, restoring neuronal protein synthesis rates, enabling a boost of memory and preventing neurodegeneration in mice models.

In summary of the systematic review, 12 of 16 clinical studies demonstrated a neutral or even a beneficial effect of trazodone on cognitive functions. The majority of these studies demonstrated a positive effect that is possibly not due to the direct effects of trazodone on cognition, but is instead mediated through an improvement in sleep disorders and depressive symptoms.

The results also highlight the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and longitudinally long-term use with prevention of cognitive deterioration.

None of the studies evaluated its effects on the UPR pathway, and there was no evidence that trazodone could be used as an active treatment of neurodegenerative diseases itself, although this review suggests that trazodone can be integrated into the therapeutic arsenal in these cases as a safe and well-tolerated adjuvant treatment for dementia comorbidities, with minimal adverse events.

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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 does not have a single cause, on the contrary every case of ALS is probably induced by a combination of factors that will lead to cellular stress. The response to this cellular stress (UPR and others) involves the shutdown of functions that are essential for the proper functioning of the body. Indeed in a state of stress response, there is no more protein production, while the protein consumption resulting from metabolism is continuing, so muscle mass is gradually destroyed.

Scientists know how to chemically or biologically induce conditions similar to ALS in model animals. One of the possibilities is to use β-Methylamino-L-alanine, or BMAA. It is a toxin from a cyanobacterium. Cyanobacteria are well known by the nickname green algae, which can be found in all places where there is stagnant water including maritime bays like that of Morlaix in France, the tidal bore of the Petitcodiac river (where there is currently an epidemic of unknown neurological disease) or aquariums. enter image description here

But toxins are not only found in standing water, they are found everywhere in the natural environment. For example, between 1990 and 2018, 14 cases of amyotrophic lateral sclerosis (ALS) were diagnosed in residents and visitors with a second home in a mountain hamlet in the French Alps. enter image description here (Frederic Coune)

A systematic investigation was then carried out. The official report is quite disappointing. It asserts that it is not possible to hypothesize that there is a link between the cases of ALS observed and a particular risk associated with this place. The report goes on to say, and this is obviously comfortable for the French administration, that there is no specific management measure whose implementation can prevent the onset of this disease.

Recent on-site investigations by Lagrange, Spencer and other colleagues from France and the United States, however, showed that all the patients had ingested wild mushrooms, especially poisonous false morels. Half of these patients had consumed Gyromitra gigas mushrooms.

Consumption of the neurotoxic fungus containing gyromitrin Gyromitra sp. (false morel), has sometimes been implicated in the sporadic genesis of amyotrophic lateral sclerosis.

There are several fungal toxins that can cause organic damage in the human body. Tricholoma equestre may contain myotoxin and repeated ingestion may cause severe rhabdomyolysis. Ingestion of Amanita smithiana and A. proxima causes kidney damage. Gyromitrin, a toxic compound that is converted to hydrazines in the stomach, is present in some species of Gyromitra. It is primarily neurotoxic, but can also induce moderate liver damage and hemolysis.

Gyromitrin is a toxin and carcinogen found in several members of the fungal genus Gyromitra, such as G. esculenta. Poisoning causes nausea, stomach cramps, and diarrhea, while severe poisoning can lead to seizures, jaundice, and even coma or death. The gyromitrin content of false morels is said to be between 40 and 732 milligrams of gyromitrin per kilogram of mushroom (wet weight). The median lethal dose (LD50) of gyromitrin is 30 to 50 mg / kg in humans. That is, in some cases a hundred grams of the fungus would be enough to reach the lethal dose.

Scientists have even shown that high consumption of fresh or dried true morels Morchella spun causes temporary neurological syndrome (SN) with cerebellar signs. For safety, they recommend to avoid consuming real morels or button mushrooms raw or undercooked, fresh or dried.

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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.

This blog mainly deals with the three main neurodegenerative diseases, Alzheimer's, Parkinson's and ALS. Unfortunately, in real life, neurodegenerative diseases do not have textbook like, well-differentiated symptoms. When Parkinson's and ALS are often associated with dementia, in scientific literature it is less common to associate Parkinson's and Autism. enter image description here

A recent prepublication article on MedRxiv, written by Kadalraja Raghavan, Samuel JK Abraham and colleagues from India and Japan, indicates that a diet derived from a black fungus may have alleviated the symptoms of autism in children with severe symptoms, and even more surprisingly, it may have lowered their level of α-synuclein in their blood.

No mechanism, intervention or therapy has proven its ability to regulate α-synuclein levels. In this study, plasma α-synuclein levels showed a significant increase after Nichi Glucan supplementation.

Parkinson's disease is a progressive neurodegenerative disease characterized by resting tremors, rigidity, postural instability, and bradykinesia.

Parkinson's disease can also present a wide range of non-motor symptoms, such as autonomic dysfunction, cognitive impairment, sleep disturbances, and neuropsychiatric symptoms, including depression, anxiety, and repetitive or obsessive-compulsive behaviors.

Parkinson's disease is characterized by intracellular inclusions comprising dozens of proteins but mainly α-synuclein. The dopaminergic neurons with their long disproportionate axons that are projecting from substantia nigra (SN) into the striatum are very vulnerable to those protein aggregates.

Autism spectrum disorders are characterized by disorders of social interaction and repetitive and stereotypical behaviors. Additional features that may accompany autism spectrum disorders are motor abnormalities, gastrointestinal issues, epilepsy, intellectual disability, or sleep disturbances.

Although α-synuclein is an intracellular protein predominantly located in the brain, several studies have reported its presence in plasma as well as in cerebrospinal fluid (CSF). The levels of α-synuclein are known to be significantly lower in patients with autism spectrum disorders than in healthy controls.

Measuring α-synuclein in CSF would give more accurate results, but this procedure is invasive and is not ideal for routine monitoring.

In this new, prospective, open-label, two-arm pilot clinical trial, six children with ASD received conventional treatment including corrective behavioral therapy and L-carnosine 500 mg per day, and 12 children received a supplementation of 0,5 g of Nichi Glucan twice a day in addition to the conventional treatment. There was only one female subject in both groups. The study lasted 90 days. Only one child had possible mild side effects related to increased stools for a week.

Subjects included in the study had been diagnosed with ASD by a developmental pediatrician, a diagnosis verified by a psychologist using a clinical interview for a behavioral model that incorporated the Childhood Autism Rating Scale (CARS).

The four children in the control group were in the severe autism category and their mean baseline score was 42.75 ± 5.76. Of the nine children who consumed Nicho glucan, two of them had mild to moderate autism (mean = 33.5 ± 2.5), while the remaining seven were in the severe autism category (mean = 43.71 ± 4.80). After the intervention, the mean CARS score in the four children in the control group was virtually unchanged at 42.5 ± 5.4.

In the Nichi Glucan group, the mean CARS score in the two children with mild to moderate autism was unchanged at 32.5 ± 0.5, while in the other seven children the CARS score improved. slightly (mean = 40.1 ± 5.96).

In the latter group, there was a visible subjective reduction in irritability and anger, improvement in sleep, speech characteristics, and improved caregiver responses.

α-Synuclein has recently been considered one of the important biomarkers for the diagnosis of autism and ASD, where levels are low compared to controls of the same age (Kadak et al., 2015; Sriwimol et al. ., 2018; Siddique et al. 2020). Plasma α-synuclein levels were significantly higher in the Nichi Glucan group than in the control group.

After the operation, plasma α-synuclein levels increased on average by 26.72 ng/dl. Human α-synuclein plasma levels were measured in peripheral blood at baseline and at the end of the 90-day study.

Β-glucans are polysaccharides naturally present in the cell walls of cereals, bacteria and fungi. The β-glucans found in yeast cell walls contain a 1.3 carbon backbone with elongated 1.6 carbon branches. Nichi Glucan, is a food supplement containing β-1,3-1,6-Glucan produced by black yeast (strain AFO-202).

At dietary intake levels of at least 3 g per day, the β-glucan in oat fiber lowers blood LDL cholesterol levels and thus may reduce the risk of cardiovascular disease. Β-Glucans are also used in various nutraceuticals and cosmetics.

It should be noted that Dr. Abraham is a shareholder in GN Corporation, Japan which in turn is a shareholder in the manufacturing company of the AFO 202 Beta Glucan

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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.

The insulin signaling pathway plays a crucial role in regulating the growth and metabolism of neurons. Deregulation of IGF-R signaling has been linked to a variety of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease.

However, the role of insulin signaling in C9orf72 ALS / FTD is not yet clear. A positive correlation of the incidence of ALS with early-onset type 1 diabetes has been reported, and a decrease in insulin and IGF-1 in the blood and cerebrospinal fluid of patients with ALS, although the relevance of these findings to disease progression is unclear.

Intrathecal administration of IGF-1 improved motor performance, delayed disease onset, and prolonged survival in the SOD1G93A mouse model of ALS. However, three clinical trials of IGF-1 administered subcutaneously in ALS have reported conflicting results. The contradictory result of these trials may be due to insufficient administration of drugs to the brain and spinal cord and the fact that ALS has heterogeneous genetic risk factors.

Atilano, Isaacs, Partridge, and colleagues have shown in a recent article that insulin/IGF signaling is reduced in C9orf72 fly models using adult brain RNA sequencing. They further demonstrated that activation of insulin/IGF signaling can attenuate several neurodegenerative phenotypes in flies expressing expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR.

Poly-GR levels are reduced when components of the insulin/IGF signaling pathway are genetically activated in diseased flies, suggesting a rescue mechanism. This effect on poly-GR levels was confirmed in a mammalian cell model. Modulation of insulin signaling in mammalian cells also lowers poly-GR levels. Remarkably, the systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Their data suggest that modulation of insulin/IGF signaling may be an effective therapeutic approach against C9orf72 ALS/FTD.

PTEN acts as a tumor suppressor gene through the action of its protein phosphatase product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too quickly. It is a target of many anticancer drugs. Pten reduction has also been reported to reduce the toxicity of C9orf72 repeats expressed in a mammalian cell line, again in agreement with the results described by scientists and the potential therapeutic benefit of modulating this pathway. It is also interesting to note that the process of brain aging has been linked to decreased insulin signaling as well as impaired insulin binding, which may partly explain why aging is a problem. risk factor for the disease.

The authors found that intrathoracic insulin administration prolonged the survival of flies expressing G4C2 repeats. Although robust, the lengthening of the lifespan was relatively modest, which could be explained by the transient nature of the insulin treatment. Insulin and IGF-1 ligands have already been tested in neurodegenerative diseases.

Overall, the researchers' study suggests that modulation of the insulin / IGF signaling pathway could be an effective therapeutic intervention against hexanucleotide repeat extension associated with C9orf72 neurodegenerative diseases, with InR being a genetic modifier. It will be interesting in the future to study the need for downstream effectors of insulin signaling in the rescue of toxicity. It is important to note that in the Drosophila, there is a single insulin-like system that has the dual function of insulin / IGF signaling; thus, the mechanism of toxicity described in the researchers' model could also be linked to IGFs. Therefore, it will be important to test whether treatment with insulin or IGF can save the survival of other C9orf72 ALS / FTD vertebrate model organisms.

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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.

In March 2021 the European drug agency granted Orphan status to Ganglioside GM1 for treatment of ALS. It was presented by 3R Pharma Consulting GmbH, a consultancy organization acting as proxy for another organization. Why the European drug agency granted Orphan status is still unknown, but it seems that this agency is much more permissive than it's US counterpart, the FDA.

By coincidence, a new article on June 12, was about how ganglioside GM1 may be the cause of Guillain–Barré Syndrome after infection. enter image description here

The quality of life after an attack of Guillain–Barré syndrome can be significantly impaired. About a fifth of patients are unable to walk unaided after six months, and many experience chronic pain, fatigue and difficulty with work, education, hobbies and social activities. But usually quality of life improves significantly in the first year. Yet in 5% of cases Guillain–Barré syndrome (GBS) can lead to death as a result of many complications.

While GBS is a disease of the peripheral nervous system, ALS is a disease of the motor tracks in the central nervous system. Yet, many patients with ALS also recount that their disease started with an infection.

Some investigators have suggested that mechanisms resulting from molecular mimicry between viral proteins and human proteins participate in the pathogenesis of GBS.

Ganglioside GM1 has important physiological properties and impacts neuronal plasticity and repair mechanisms, and the release of neurotrophins in the brain. Because of GM1's close role in neuron repair mechanisms, it has been investigated as a possible drug to slow or even reverse the progression of a wide range of neurodegenerative conditions. Controlled phase II studies have indicated that GM1 can ease the symptoms of Parkinson's disease

Weirdly for the complement immune system GM1 is sometimes identified as a virus fragment.

Alas Ganglioside GM1 is not the sole case of autoimmunity. Many autoimmune diseases, some of them ALS mimics, are caused by autoantibodies. An autoantibody is an antibody produced by the immune system that is directed against one or more of the individual's own proteins.

To complicate the matter, some autoantibodies are needed to maintain tissue and protein homeostasis through adaptive debris clearance. For example autoantibodies against TDP-43 are found lacking in Patients With Amyotrophic Lateral Sclerosis.

Autoantibody tests may be ordered as part of an investigation. ANA is a marker of the autoimmune process – it is positive with a variety of different autoimmune diseases but not specific. Consequently, if an ANA test is positive, it is followed up with other tests.

Plasmapheresis and intravenous immunoglobulins (IVIG) are the two main immunotherapy treatments for GBS. Plasmapheresis attempts to reduce the body's attack on the nervous system by filtering antibodies out of the bloodstream. Similarly, administration of IVIG neutralizes harmful antibodies and inflammation.

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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.

Several articles have recently appeared that should make the pharmaceutical industry reflect on the value of therapies that suppress human proteins or decrease the expression of human genes.

This is the case, for ASOs, this is also the case for the many proposals for immunotherapies against human proteins. We obviously remember the hundreds of unsuccessful clinical trials against ALS or Parkinson's, and the 2,500 unsuccessful trials against Alzheimer's disease.

How did we get there?

In the past 30 years many neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), have been correlated with DNA damage, resulting in incorrect RNA sequences and therefore poorly translated proteins.

Although initially scientists postulated a mechanism of loss of function (the mutated protein having lost its function). At the turn of the century they realized that this was not a plausible explanation, so they expressed the hypothesis of a gain of function. Which is much more difficult to refute. But this hypothesis is attractive because a gain of function mechanism can be easily suppressed with ASO or immunotherapy.

Case of a vaccine against the Tau protein

For example, the results of a phase II trial of AADvac - a vaccine against pathologic forms of the tau protein - were published on June 14 in Nature Aging by Petr Novak and colleagues.

This vaccine met its primary endpoint in this Phase II study, so it appears reasonably appears safe. It also elicited antibody responses in almost all of the participants, who were diagnosed with mild Alzheimer's disease, and attenuated a gradual increase in plasma NfL over the two-year trial.

By analyzing cerebrospinal fluid samples taken from a small subset of volunteers, the scientists were able to confirm that the vaccine reduced the concentration of Tau protein in the cerebrospinal fluid.

Unfortunately, as usual, the vaccine did not slow the cognitive decline of the patients.

Case of an ASO against C9orf72

Antisense oligonucleotide therapy are strands of RNA that prevent protein translation of certain strands of messenger RNA by binding to them, in a process called hybridization.

Researchers led by Rita Sattler of the Barrow Neurological Institute in Phoenix and Robert Baloh of Cedars-Sinai Medical Center in Los Angeles carried out experiments to suppress the C9orf72 gene on a laboratory mouse model that reproduces the disease Alzheimer's disease, or at least the appearance of amyloid plaques.

enter image description here

Baloh and his colleagues previously reported in 2016 that in myeloid cells from C9orf72 knockout mice and C9 carriers with ALS / FTD, reporting of lysosomal function leads to escalation of interferon and increased inflammation.

To determine how C9orf72 deficiency affects the way microglia processes plaques and synapses, the researchers made an Alzheimer mice model deficient in C9orf72 expression.

In 3-month-old mice, which begin to develop amyloid plaques, scientists did not detected any obvious effect of C9orf72 deficiency on plaque deposition.

However, at 6 months, the mice lacking C9orf72 had fewer plaques, and those that remained were smaller and more compact than the aggregates of the control mice. Approximately twice as many microglia gathered around each plaque as in the control mice.

At the end of the experiment, the C9orf72 knockout mice had fewer plaques, these were smaller, but neurons had fewer synapses due to overzealous pruning performed by the microglia.

Conclusion

One can only wonder at the interest in therapies that suppress human proteins or decrease the expression of human genes. By what conceptual leap, or by what blindness are we led to think that a potentially deleterious mechanism can become a successful therapy?

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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.

Metabolic disorders are associated with the progression of amyotrophic lateral sclerosis. This new study by Tanya S McDonald and colleagues from the University of Queensland is very interesting because it focuses on physiology and not on molecular phenomenas.

Throughout the progression of ALS disease in laboratory mice, researchers have identified increased glucose uptake, possibly due to insulin-independent mechanisms. This glucose was then stored as glycogen in tissues such as the liver, rather than being used as an energy source. This might explain ALS' hypermetabolism.

Normally, in a healthy human, the postprandial state (after-meal) elevates glucose levels and triggers the release of insulin from the pancreas. As insulin levels rise, there is an increase in glucose uptake and then storage of excess glucose in peripheral tissues.

Glycogen is one of two forms of energy storage, with glycogen being short-term storage and the other being triglyceride stores in adipose tissue (i.e. body fat) for long term storage.

Patients with ALS cannot maintain their weight, and experience rapid muscle loss. Curiously, this muscle loss is not the subject of much attention from scientists who are interested only in motor neurons. They often deplore a lack of biomarkers, while the loss of muscle mass is an obvious biomarker. This article suggests that ALS is a form of diabetes, although this is not formally expressed in the article.

Rapid weight loss in patients with ALS is associated with rapid disease progression, while conversely, a higher body mass index (~ 27) tends to increase the survival rate. Studies also suggest that insulin resistance plays a role in disease progression in patients and animal models of ALS.

Glucose homeostasis is fundamental for the human body and is mainly regulated by the levels of 4 major hormones: 1. Insulin 2. Glucagon 3. Cortisol 4. Epinephrine The ratios of these circulating hormones will dictate the activity of specific metabolic pathways that control glucose homeostasis. There are many other hormones (thyroid hormone, growth hormone, etc.) and adipokines (adiponectin, leptin, etc.) that can influence glucose homeostasis, as well as neural mechanisms that control higher level functions such as hunger and satiety.

Insulin secretion depends on oxidative metabolism. In humans, glycogen is made and stored primarily in liver cells and skeletal muscle cells.

SOD1G93A mice exhibit loss of body weight and lean body mass with reduced activity and increased oxygen uptake in the mid-symptomatic stage of disease.

McDonald and his colleagues first investigated whether the weight loss frequently observed in SOD1G93A mice was due to reduced food intake or increased energy expenditure.

At the onset of the disease, the mice showed no difference in body weight, but still had a 10% loss of their lean body mass (body mass other than fat, including bones, muscles, blood, skin, etc.). That is, fat was substituted for muscle mass.

At the mid-symptomatic stage, the SOD1G93A mice weighed significantly less than their normal counterparts, with a loss of 8 and 10% of total body weight and lean body mass, respectively.

However, the total food intake was similar between normal mice and SOD1G93A mice at these two stages of the disease.

While at the initial stage there was no difference in oxygen uptake between mutated and normal mice, at the mid symptomatic stage the mean oxygen uptake in SOD1G93A mice was significantly higher than in normal mice.

This increase in oxygen uptake in the mid-symptomatic stage was not, however, due to an increase in average locomotor activity, as the reduction in locomotor activity was only measured during the dark cycle in the dying stages. onset and semi-symptomatic. Indeed, during the light phase, the mid-symptom SOD1G93A mice were 126% more active than their normal counterparts.

No correlation was found between the decrease in lean body mass and the average oxygen uptake over a 24-hour period.This increase in oxygen uptake at the mid-symptomatic stage is therefore unexplained.

Exogenous glucose uptake is increased in SOD1G93A mice at the mid-symptomatic stage of the disease

The scientists then set out to determine whether glucose management was impaired in SOD1G93A mice. At the onset of symptoms, SOD1G93A mice and their normal counterparts responded similarly to glucose. However, in the mid-symptomatic stage of the disease, SOD1G93A mice showed a faster rate of blood glucose clearance.

The authors then confirmed that the loss of body weight in SOD1G93A mice was not responsible for the decrease in blood glucose concentration. Although the baseline insulin concentration remained unchanged, the response of plasma insulin to exogenous glucose was significantly lower in SOD1G93A mice, with a 44% reduction in insulin concentrations.

At the onset of the disease and at its mid-symptomatic stage there was no difference in the immunoreactive zone of the glucagon-positive cells. But at the mid-symptomatic stage McDonald and his colleagues found in the pancreas of SOD1G93A mice, a 22% reduction in insulin-positive β cells compared to the pancreas of normal mice.

Despite this difference in baseline blood glucose concentrations, normal and SOD1G93A mice responded similarly to insulin. This is a major difference between diabetes and ALS.

Although the SOD1G93A mice weighed less at onset and during the middle of symptoms, the amount of insulin did not correlate with the inverse of blood sugar levels. This indicates that the detection of oxidative metabolism was inoperative, which is one of the characteristics of diabetes.

In addition to insulin and glucagon levels, the authors also demonstrated that glycogen concentrations were 210 and 480% higher in the liver of SOD1G93A mice at onset and mid-symptom stages, respectively.

Insulin tolerance is not affected in SOD1G93A mice, despite decreased fasting blood sugar

After an overnight fast, the accumulation of glycogen in the liver was still 400-500% higher in SOD1G93A mice amid symptoms compared to their normal counterparts. These changes are insulin independent because there was no difference in the elimination of glucose in response to exogenous insulin. In addition, SOD1G93A mice exhibit reduced insulin-expressing cell surface area and impaired insulin release in response to exogenous glucose. SOD1G93A mice also showed an accumulation of glycogen in the liver, despite increased circulating glucagon concentrations and gene expression data, suggesting a decrease in both glycogen synthesis and degradation.

This indicates that glucagon signaling may be altered in the liver of SOD1G93A mice. Finally, the gene expression profile of several metabolic enzymes suggested that the liver switches from using glucose to fatty acids as an energy source, which has already been found in skeletal muscle and CNS tissues in the body. SLA.

This confirms the results in other affected tissues which show a shift from the use of glucose to lipids as the primary fuel source for the TCA cycle. Although the exact trigger that leads to this change is unknown, it has been proposed that an increase in fatty acid metabolism occurs to compensate for the inability of tissues to use glucose and glycogen as energy substrates. Although this is a beneficial short-term compensatory mechanism, chronic dependence on fatty acid metabolism via β-oxidation can lead to the accumulation of toxic byproducts, especially reactive oxygen species. (ROS).

Conclusion What is described in this article is a reminder of the evolution of diabetes. When diabetes begins, the pancreas normally produces insulin. Muscle cells preferably use fatty acids as an energy source. Gradually the cells of the body responsible for collecting and using glucose become insensitive to insulin. Since glucose cannot enter the cells, the beta cells of the islets of Langerhans in the pancreas will produce more insulin to force the cells to take up glucose. In this article the mechanism is a little different, instead of making more insulin, the body stores glucose in the form of glycogen. The more diabetes progresses, the more beta cells are depleted, until they disappear. This disappearance was also noted in the article.

However, this does not explain the local appearance of the onset of ALS and the geographical progression of the disease, and it is a work on model mice for ALS. It is known that work on mice is rarely transferable to humans, particularly for neurodegenerative diseases.

Yet, this article is unique. This is an article that talks about physiology, it does not appeal to obscure molecules that are arbitrarily assigned biological roles, it suggests a mechanism for ALS that is down to earth.

Of course there are still many unknowns as to why ALS often starts with a specific muscle and then progresses. We don't know how to treat diabetes any more than we do with ALS, but I believe that an important step has been accomplished.

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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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