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

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

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

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

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

[0] https://www.ncbi.nlm.nih.gov/pubmed/31900865

Advertisement


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

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

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

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

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

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

enter image description here

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

Advertisement


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

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

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

enter image description here

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

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

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

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

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

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

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

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

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

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

Advertisement


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

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

enter image description here

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

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

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

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

https://www.ncbi.nlm.nih.gov/pubmed/31875556

Advertisement


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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

https://elifesciences.org/articles/43302

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

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

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

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

Advertisement


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

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

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

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

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

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

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

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

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

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

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

Advertisement


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.

NeuroD1 will be tested to restore lost neurons in a nonhuman primitive model of Alzheimer's disease.

Neurogenic differentiation 1 (NeuroD1) is a transcription factor of the NeuroD type. It is encoded by the human gene NEUROD1. It regulates the expression of the insulin gene and mutations in this gene lead to type II diabetes.

Who's working on it

Several scientists from Chen Laboratories have discovered that NeuroD1 converts reactive glial cells into functional neurons in the mouse brain.

enter image description here

There were three articles, one in 2014 by Guo and his colleagues. They had indicated that a single transcription factor, NeuroD1, could reprogram astrocytes into neurons, providing a potential way to reconstruct neurons in the late stages of the disease.

This year, Chen announced that NeuroD1 had restored function after a stroke in mice and non-human primates after splicing into an AAV9 vector and injected into the brain.

And another article was submitted by Ge and his colleagues. Researchers are now thinking of using this strategy (NeuroD1 to restore neurons and other cells) in Alzheimer's disease.

How does NeuroD1 work?

Gong Chen and his colleagues believe that: "One reason that so many Alzheimer's trials have failed may be that too many neurons have already been lost."

NeuroD1 did this by creating not only new neurons, but also astrocytes, as it encourages astrocytes to divide and differentiate. The new astrocytes seemed to attract new blood vessels. "Essentially, we're regenerating new neural circuits," Chen said.

Could AAV-NeuroD1 work against Alzheimer's disease?

Chen and his colleagues have tried it in 5xFAD mice (an animal model with Alzheimer's disease). "We have regenerated millions of new neurons throughout the brain," Chen said. The neurons survived for at least eight months, while the number of reactive astrocytes decreased. AAV vector-treated mice remember better and find a hidden platform in an aquatic labyrinth more rapidly than untreated control mice.

Chen's team is currently testing the vector in a model of Alzheimer's disease in non-human primates in China.

And for ALS?

Chen hopes the strategy using NeuroD1 with viral load administration will also work in other diseases. His team has previously tested that AAV-NeuroD1 vectors restore motor neurons throughout the spinal cord and improve motor skills when injected into the spinal cord of mice carrying the G93A SOD1 mutation.

Advertisement


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 presence and density of the repeater F waves are mainly related to the degree of loss of LMN and they show no obvious correlation with the UMN system malfunction

In neuroscience, an F wave is the second of two voltage changes observed after the application of electrical stimulation to the surface of the skin above the distal region of a nerve. F-waves are often used to measure nerve conduction velocity and are particularly useful for assessing conduction problems in the proximal region of the nerves (ie, nerve portions close to the spinal cord).

They are almost universally used for the diagnosis of ALS. At the same time ALS patients have often complained about the quality of this review, which regularly leads to incorrect diagnoses. A new article by Akarsu and his colleagues shows that other techniques using the same tools are more accurate. It may even be that in the long term we are reexamining the statement that ALS is a disease affecting both upper and lower motor neurons.

In a typical F wave study, a strong electrical stimulus is applied to the surface of the skin above the distal portion of a nerve, so that the pulse travels both distally (towards the muscle fiber). ) and proximal (to the motor neurons of the spinal cord).

These impulses are also called orthodromic and antidromic, respectively. When the orthodromic stimulus reaches the muscle fiber, it causes a strong response in M ​​indicating muscle contraction. When the antidromic stimulus reaches the motoneuron's cell bodies, a small part of it turns against it and an orthodromic wave descends from the nerve to the muscle.

This reflected stimulus evokes a small proportion of muscle fibers, resulting in a second group of near-simultaneous action potentials from several muscle fibers in the same area, called the F ** wave.

Electrophysiological biomarkers have allowed extensive work to detect and quantify upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction in amyotrophic lateral sclerosis. Neurophysiological index and motor unit number estimation (MUNE) methods have been widely used as potential biomarkers of LLN loss.

The neurophysiological index has been suggested to demonstrate the loss of LML in patients with ALS, even in presymptomatic muscles, and has been shown to be sensitive to the detection of disease progression. Although several MUNE methods and transcranial magnetic stimulation with single pulses and matched impulses have been proposed since the invention of the first technique in 1971, none of them has been accepted as a standard method because of the various inherent limitations. to the technique.

In ALS, a disease affecting both UMN and LMN, cortical and peripheral mechanisms have been proposed to explain F-wave abnormalities. An increase in the number of repeater F waves in the presence of clinical involvement of the UMN has been reported in ALS. On the other hand, it was found that the atrophied muscles, more marked in the thenar region, generated more repeater F waves, which is consistent with the division of the hand that occurs in the same disease.

Overall, the mechanism for generating repeater waves is still discussed.

In the present study, the authors aimed to study repeated F waves in the thenar and hypothenar muscles of patients with ALS and their correlation with other electrophysiological markers to better understand the dominance of the dysfunction of the UMN or LMN in the mechanism of their emergence.

Their results, taken as a whole, suggest that the presence and density of the repeater F waves are mainly related to the degree of loss of lower motor neurons.

In response to the progressive loss of motor neurons, reinnervation intervenes to compensate and the results of these dual processes establish the diagnostic features of ALS. The reduced number of motoneurons in the generation of F waves gives rise to a greater number of repeater F waves. On the other hand, the large F waves and giant F waves of the repeater have been associated with re-innervated motor units.

An earlier study showed that the frequency of repeater F waves was increased in ALS patients with pyramidal signs compared to the non-pyramidal group. The authors therefore divided the groups of patients according to the presence or absence of pyramidal signs and did not use a quantitative tool to determine the involvement of the corticospinal tract.

F-wave studies in UMN-only diseases, such as multiple sclerosis and cerebrovascular disease, have shown an increase in the persistence, amplitude, duration, and latency of the F-wave. but none of these studies studied repeated F waves.

According to their results, the ALSFRS-R and MRC sum scores were not correlated with the F-wave repeat parameters. These clinical scores provide an overall functional assessment in patients with ALS.

In addition, the ALSFRS-R UL score, the ALSFRS-R sub-score addressing upper limb function, also revealed no correlation.

This suggests that clinical scores are less reflective of motoneuronal loss, possibly due to the remanent capacity of the motor system, and that repeater F waves may provide an earlier measure of motor neuron degeneration, as most electrophysiological methods do. on this subject.

Conclusion

Their overall results suggest that the presence and density of the repeater F waves are mainly related to the degree of LLN loss and they do not show any obvious correlation with the UMN network malfunction.

Advertisement


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.

TDP-43 and spinocerebellar ataxia type 31 (SCA31)

Spinocerebellar ataxia (SCA) is a progressive degenerative genetic disease that occurs in about 30 different forms, each of which can be considered a neurological condition in its own right. There are as many people diagnosed with spinocerebellar ataxia as there are people diagnosed with ALS. SCA is hereditary, progressive, degenerative and often fatal. Curiously for a disease whose origin is clearly genetic, there is no effective treatment on the market.

One recent publication alludes to the role of TDP-43 in certain neurodegenerative diseases. TDP-43 acts as an RNA chaperone against toxic proteins.

SCA can affect anyone at any age. Symptoms include non-cerebellar features, such as parkinsonism, chorea, pyramidalism, cognitive disorders, peripheral neuropathy, seizures, among others. As with other forms of ataxia, SCA frequently causes atrophy of the cerebellum, loss of fine coordination of muscle movements resulting in unstable and clumsy movement, and other symptoms.

As with ALS, the symptoms of ataxia vary by type and patient. In many cases, a person with ataxia retains full mental capacity but gradually loses physical control.

Unlike ALS, the causes of which are unclear, most types of ACS are caused by a recessive or dominant gene. In many cases, people do not know that they carry a relevant gene before having children begin to show signs of the disease.

Kinya Ishikawa and Yoshitaka Nagai were interested in spinocerebellar ataxia type 31 (SCA31), which is one of the dominant autosomal neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom.

This disease is caused by a complex long pentanucleotide repeat of 2.5 to 3.8 kb (TGGAA), (TAGAA), (TAAAA) and (TAAAATAGAA) in an intron of the gene called BEAN1, which is expressed in the brain and associated with Nedd4.

By comparing various pentanucleotide repeats in this particular locus among the Japanese and Caucasian control populations, it was found that (TGGAA) was the only sequence correlated with SCA31.

This complex repetition also resides in the intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that complex repetition is bidirectionally transcribed as non-coding repeats.

In the human brain with SCA31 variant (UGGAA), it was found that the BEAN1 transcript of the SCA31 mutation formed abnormal RNA structures called RNA foci in Purkinje cells of the cerebellum.

enter image description here * By BrainsRusDC - Personal work, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=64271015*

RNA reduction analysis subsequently revealed that (UGGAA) binds to the TDP-43, FUS and hnRNP A2 / B1 RNA binding proteins.

In fact, it has been found that TDP-43 co-localizes with RNA foci in human Purkinje SCA31 cells. To dissect the pathogenesis of (UGGAA) in SCA31, the authors generated SCA31-like transgenic fly models by overexpressing the pentanucleotide repeats of the SCA31 complex in Drosophila. They found that the toxicity of (UGGAA) depends on the length and level of expression and that it is attenuated by the co-expression of TDP-43, FUS and hnRNP A2 / B1. Further investigation revealed that TDP-43 improves toxicity (UGGAA) by directly correcting the abnormal structure of (UGGAA).

This led them to propose that TDP-43 act as an RNA chaperone against toxic substances (UGGAA) n. Further research on the role of RNA binding proteins as RNA chaperones could provide a new therapeutic strategy for SCA31, or even for other TDP-43 type proteopathies.

Advertisement


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.

Please, to help us continue to provide valuable information: