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.

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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 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.

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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.

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.

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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.

Normal control of insulin and glucagon secretion by pancreatic islets is essential for maintaining glycemic homeostasis and it becomes defective for all forms of diabetes mellitus. There are poorly understood relationships between ALS and diabetes, just as between ALS and cancer.

We have known for a long time that about half of patients with ALS are insulin-resistant. This is also the case in other neuro-degenerative diseases such as Alzheimer's or Kennedy's disease. A recent article involves a neurotransmitter in the regulation of insulin.

The role of the inhibitory neurotransmitter GABA (γ-aminobutyric acid) in controlling the secretion of pancreatic islet cells has been known for a long time. GABA is released into pancreatic β cells by both synaptic-type microvesicles and large, dense central vesicles under glucose control, and the secreted amino acid subsequently blocks the release of glucagon by α4 cells.

enter image description here Source: Blausen.com staff (2014). "Medical gallery

By acting as an autocrine messenger and binding to its receptors on β-cells, GABA can also curb insulin secretion. However it was not understood how the neurotransmitter could enter or leave the cell through the plasma membrane. Menegaz and his collaborators show in their article, that GABA is mainly present in human islets in the cytosol of β and δ cells, but not α cells. In addition, the authors found a decrease in GABA levels in samples of patients with type 1 or type 2 diabetes, potentially contributing to the exaggerated release of glucagon observed in these diseases. While this was not reported in this study, patients with ALS have significantly lower levels of GABA in the motor cortex than healthy people.

An important aspect of the new study is the identification of probable molecular mediators of GABA uptake and release by β-cells. By searching published databases of known proteins carrying GABA, the authors showed that TauT was both detectably expressed and localized to the plasma membrane in human β cells. Another carrier, Slc LAT2 family member, has also been involved as a carrier of a GABA mimetic.

The authors then explored the potential role of intraball GABA in the control of hormone secretion, showing that a decrease in β-cell synthesis of GABA increases insulin secretion. In contrast, exogenously added GABA decreases insulin secretion in glucose-stimulated β cells.

Transiently, the work suggests a new therapeutic potential for the treatment of GABA in diabetes. In type 2 diabetes, agonists (or inhibitors of GABA metabolism) can modulate insulin secretion. However, in type 1 diabetes, in which β cells have been destroyed, GABA antagonists may stimulate glucagon secretion and improve the risk of life-threatening hypoglycaemia.

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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.

Searching for a TDP-43 therapy

Genetic therapies against TDP-43 aggregates had been proposed for ALS disease.

While this is certainly feasible with the current state of art (see my book), it would certainly be sold at a cost similar to Zolgensma, because of the lack of competition in the field.

The classical drug which complies with the "Pfizer rule of five" is a peptide, so a peptide that would remove TDP-43 would be desirable. Peptides are low cost and easy to procure.

Improving an already published peptide

Several scientific articles [0] are suggesting that a peptide might help in ALS by removing TDP-43 from mitochondria.

YGRKKRRQRRRAQFPGACGL

The initially proposed peptide was formed by assembling a M1 section from TDP-43 with a TAT peptide.
* The M1 section is: FPGACGL
* The M3 section is: GFGFV
* Tat is a regulatory protein that drastically enhances the efficiency of viral transcription, for example in HIV with a transition to the most dangerous form of AIDS (T-tropic).

Bioinformatics tools suggest that its biological function as a neurotoxin which blocks acetylcholine receptors. While a patent was written in 2016 (and still valid for 2019) the main scientist of the team who wrote the 2016 article, said later that this peptide was actually very toxic. This statement is not difficult to trust.

An improved peptide

If we use a peptide made simply with an altered M3 section followed by the M1 section.

Some of those peptides, are predicted by bioinformatics tools has not being a toxin, and not an antigen.

Those peptides seems to have all required qualities: * They must not be toxic * They must go through the BB barrier * They must localize in the mitochondria (where it is supposed to help remove TDP-43)

The best seems to be this one: Peptide sequence: GFGFVRPGACGL Smiles: NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)N[email protected]@(C(C)C)C(=O)N[email protected]@(CCCNC(=N)N)C(=O)N1[email protected]@(CCC1)C(=O)NCC(=O)N[email protected]@(C)C(=O)N[email protected]@(CS)C(=O)NCC(=O)N[email protected]@(CC(C)C)C(=O)O However it does not terminate entirely with FPGACGL, so it might be prudent to use also the next one below.

Peptide sequence: GFGFPFPGACGL Smiles: NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)N1[email protected]@(CCC1)C(=O)N[email protected]@(Cc1ccccc1)C(=O)N1[email protected]@(CCC1)C(=O)NCC(=O)N[email protected]@(C)C(=O)N[email protected]@(CS)C(=O)NCC(=O)N[email protected]@(CC(C)C)C(=O)O

Maximum Recommended Daily Dose (Human): 0.00124 (mmol/kg-bw/day) / 1.45 (mg/kg_bw/day)

This is not a medical advice, it is just a theoretical exercise, to see which peptide could be a candidate to offer the effect described in the following article: https://www.nature.com/articles/nm.4130

Tool for testing neurotoxin function:
https://webs.iiitd.edu.in/raghava/ntxpred
Tool for testing immunogenicity:
http://www.ddg-pharmfac.net/vaxijen/
Blast on human genome:
https://blast.ncbi.nlm.nih.gov/Blast.cgi
http://tox.charite.de/protox_II/index.php?site=faq
http://lmmd.ecust.edu.cn/admetsar2

[0] Including: The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal Toxicity Article in Nature medicine · June 2016 DOI: 10.1038/nm.4130

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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 are many questions about how TDP-43 can be deleterious in ALS disease. Normally TDP-43 is involved in many repairing or protecting scenarios. In 2013 scientists proposed that misplaced TDP-43 was killing mitochondria, by disturbing their fission/fusion processes (mitochondria are very dynamic structures). However this is not the scientific consensus.

A scientific article published on October 30, 2019 about Alzheimer's disease confirms the effect of a peptide against the aggregation of TDP-4 in mitochondria. This peptide and others were already described in a 2016 ALS publication.

The molecular mechanisms by which TDP-43 contributes to the pathology of ALS remained elusive. In the 2016 article, the authors wrote that they found that TDP-43 accumulated in neuronal mitochondria in subjects with ALS or frontotemporal dementia. Neurodegenerative diseases are characterized by cytoplasmic localization of TDP-43 in granule types. The 2016 study directly linked the toxicity of TDP-43 to mitochondrial metabolism and proposed targeting the mitochondrial localization of TDP-43 as a promising therapeutic approach for ALS.

The authors of the 2019 study (Gao et al.), demonstrate that one of the two mitochondrial TDP-43 inhibitory peptides of the 2016 article, when administered late in the course of the disease, may attenuate the development and progression of cerebral neuronal loss and behavioral deficits in the 5XFAD transgenic mouse model in Alzheimer's disease.

If this peptide is effective against TDP-43 proteinopathies, it is a real breakthrough because a peptide is something that is easy to produce at a low cost.

In neurodegenerative diseases, TDP-43 is localized in the cytoplasm as well as in mitochondria that may be free in the cytoplasm or anchored in the endoplasmic reticulum, where it gives it the "raw" appearance of the endoplasmic reticulum.

TDP-43 or truncated forms of TDP-43 may be present inside or outside the mitochondria. The portion of the total length of TDP-43 within the mitochondria can bind to the subunits encoding the mitochondria-mediated messenger RNA (mRNA), whereas the truncated TDP-43 lacks the locating sequence. mitochondrial M1 is limited to the inner membrane space no effect on ND3 / 6 expression or mitochondrial function.

The mitochondrial localization of TDP-43 is dependent on its M1 motif, the deletion of which suppresses its mitochondrial accumulation. The PM1 synthesized peptide (YGRKKRRQRRRAQFPGACGL) in which the M1 motif was fused to the TAT peptide (GRKKRRQRRR), competitively inhibits the mitochondrial localization of TDP-43 and suppresses the TDP-43 induced toxicity on mitochondria.

The authors used PM1, a peptidic inhibitor derived from TDP-43, as a continuous injection, to specifically reduce its expression in mitochondria. PM1 abolished TDP-43 protein kinetics, reversed neuronal loss, and reduced neuroinflammation in aged 5XFAD mice long after symptom onset. Since the amyloid plaque load was not attenuated or prevented by PM1, the authors' results clearly indicate that TDP-43 in mitochondria does not affect the pathology of Aβ.

Chronic administration of the PM1 peptide significantly attenuated TDP-43 protein kinetics, mitochondrial abnormalities, microgliosis, and even neuronal loss, but was without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. PM1 also improved cognitive and motor functions in 12-month-old 5XFAD mice and completely prevented the development of mild cognitive impairment in 6-month-old 5XFAD mice.

Beyond its involvement in Alzheimer's disease, this article corroborates the 2016 article on ALS and therefore offers hope that a continuous (insulin pump-like) delivery of a low-cost peptide could to be very beneficial for ALS.

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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 and cancer

There is a persistent mystery about the causative mechanisms of ALS. The intense work over the last two decades on SOD1 has not helped to conclusively understand its link with the disease. Many SOD1 mutations produce very similar ALS phenotypes. But these mutations have not prevented neurons from functioning properly for several decades, so it is difficult to invoke them to explain the onset of the disease. Even though there is less scientific work on FUS or TDP-43, as their discovery is more recent, the mystery is also complete on how a non-mutated and mis-located TDP-43 protein in the cytoplasm could kill a neuron. The only obvious case is that of C9orf72, where the dipeptide repeats, clearly could not produce functional protein. However, even in this case, it is unclear why ALS only occurs at an advanced age.

PARP is involved in DNA repair

There is a troubling link between cancer and ALS, for example, there is an inverse relationship between the onset of cancer and the onset of ALS. ALS medications also have anti-cancer properties. So, perhaps it's not surprising that they can share a fundamental cause: defects in DNA repair mechanisms. Poly-ADP-ribose polymerases (PARPs) are involved in DNA repair, as are FUS or TDP-43.

During DNA damage or cellular stress, ** PARP ** is activated, resulting in an increase in the amount of poly-ADP-ribose and a decrease in the amount of NAD +.

enter image description here

The poor localization of FUS and TDP-43 in the cytoplasm inhibits the mechanism of DNA repair

FUS and TDP-43 both play a role in the treatment of RNA, including splicing, transcription and transport. The involvement of FUS and TDP-43 in the response to cell genome damage has recently been discovered. In healthy neurons, FUS protects the genome by facilitating dependent recruitment of ** PARP-1 **. The authors report that TDP-43 is an essential component of the end-junction-mediated double-stranded DNA (DNA) repair pathway (NHEJ). TDP-43 is rapidly recruited to double-stranded DNA sites to stably interact with DDR and NHEJ factors, acting in particular as a scaffold for recruitment of the isolating XRCC4-DNA ligase 4 complex at DSB sites. Indeed, the presence of fragmentation of TDP-43 and its aggregation in ALS samples is strongly correlated with the presence of ** PARP-1 ** and cleaved caspase-3.

During apoptosis, PARP moves to the cytoplasm

Caspases are a family of cysteine ​​proteases that play an essential role in programmed cell death. This protease cleaves ** PARP-1 ** into two fragments, leaving it completely inactive to limit the production of poly-ADP-ribose. One of its fragments migrates from the nucleus to the cytoplasm and is considered a target of autoimmunity. At the beginning of 2019, dysregulation of PARylation was found to contribute to the pathogenesis of ALS by promoting protein aggregation.

Although PARylation occurs primarily on PARP proteins, the association of PAR with ALS-related granules has been observed.

Causal chain of ALS

The results of the scientists thus link the pathology of TDP-43 to altered repair of DSB and persistent DDR signaling in motor neuron diseases, and suggest that targeted therapies on double-stranded DNA repair could improve genome instability induced by the toxicity of TDP-43 in motor neuron diseases.

In summary the mechanism causing TDP-43 ALS would be:

  • Mutations of FUS or TDP-43 would render DNA repair ineffective.
  • The intervention of PARP would repair this DNA and relocate TDP-43 in granules in the cytoplasm.
  • This would further aggravate the problems of DNA repair.

A possible therapeutic mechanism

These new findings provide insight into how a DNA repair defect may be associated with FUS and / or TDP-43 neurodegeneration, and raises the question of whether the resolution of DNA ligation problems would be a pathway. promising for the development of neuroprotective treatments.

So mechanisms that would alleviate the burden of PARP (which is different from inhibiting it), would improve the pathology.

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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.

What is interleukin 6?

Interleukin 6 (IL6) is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. Deregulated IL6 production is implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. In addition to other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Autoimmune diseases such as rheumatoid arthritis are associated with abnormally high levels of IL-6.

enter image description here

How does it work?

IL-6 had previously been classified as a proinflammatory cytokine, but the anti-inflammatory (beneficial) effects of myokines in general of interleukin-6 of muscle origin are now recognized. So we have a cytokine that can have two modes, one beneficial, the other deleterious, how is that possible?

The explanation could be that the signaling pathways upstream and downstream of IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signaling in macrophages, which depends on activation of the NFκB signaling pathway, intramuscular IL-6 expression is regulated by a signaling cascade network, including Ca2 + / NFAT and glycogen / p38 MAPK pathways.

IL6 has 2 signaling paradigms: IL6 signaling and IL6 signaling. Although conventional IL6 signaling occurs via IL6 receptors bound to the membrane, IL6 retransformation is induced by a systemic and localized increase in the extracellular soluble IL6 receptor (sIL6R). generated by proteolytic cleavage, called "shedding," of the receptor from the cell surface. These soluble receptors can be activated by IL6 and activate signaling cascades. Thus, IL6 trans-signaling activates the IL6 signaling pathways in cells that do not express the IL6 receptor.

Are there different reactions to IL6 in humans?

In humans, there are at least two alleles for the IL6 receptor (Asp358Ala, A / C, rs2228145), the A allele (Asp358) being the main allele and the C allele (Ala358), the variant allele. The expression of the IL6 receptor (IL6R) is favored by the C allele. In individuals with IL6R allele, increased receptor expression improves both localized and systemic IL6 transsignalization in the presence of IL6. This allele is associated with certain diseases such as asthma.

Why would IL6 have an interest in treating ALS?

Perhaps because a patient with ALS was reported to have had a remission in 2014 by consuming lunasin, a soy peptide, researchers have wondered whether IL6 transsignalization could play a role. potential in ALS.

How did the scientists proceed?

IL6 and sIL6R levels were measured in samples in a cohort of patients with ALS and compared to healthy patients. Their results suggest that the IL6R C allele influences IL6 signaling in the central nervous system of patients with ALS. In a second cohort of ALS subjects with more definite clinical data, the presence of the IL6R C allele was associated with a more rapid progression of the disease. These results suggest that identifying patients with the IL6R C allele may provide useful information for predicting disease progression and identifying those who may benefit most from IL6R blocking therapies.

What happened in 2014

ALS experts will recall that in 2014 Mike McDuff, who has ALS, experienced dramatic improvements in speech, swallowing and strength in ALS. lunasin.

Dr. Bedlack from SLA Duke Clinic confirmed that Mike McDuff's symptoms had actually improved dramatically. A clinical trial was then conducted to evaluate the interest of lunasin in the case of ALS. Fifty people with ALS were put on the diet containing exactly the lunasin Mike McDuff had followed and were followed for one year. The clinical trial was completed in September 2017. Unfortunately, there is no evidence that lunasin slowed, stopped, or reversed ALS in clinical trial participants. Gastrointestinal adverse events were more frequent than expected in the trial participants, including cases of constipation severe enough to warrant hospitalization.

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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.

I did published a book on ALS research:

Caveats: I am not a doctor, nor a scientist and English is not my mother-tongue.

Here are some take home points:

  • Scientists are obsessed by SOD1 (2% of all ALS cases) as a model for ALS. However there is overwhelming evidence this is a fruitless pursuit.

  • There are nearly no treatments:

    • For all pALS, a very imperfect treatment is Nurown, but it exists!
    • For SOD1 pALS (2% of all cases), there are two treatments that are in clinical trials.
    • For the other (98%) pALS there are no drugs in the pharmaceutical pipeline. However for most pALS (TDP-43 / 95% of all cases) there are genetic therapies that have recently been published by scientists, but if no one tries to defend them, it will take another 10 years before they are marketed.
  • The ALS research is bizarre, scientists often contradict colleagues but nobody seems to care. The consensus still cites theories that have been disproved since decades, like glutamate excitotoxicity. ALS is certainly not one homogeneous disease, but it is still treated as such by scientists. Animal models of ALS have little value in translation of drugs to humans, but moreover often ALS research is done on insects (that have an exoskeleton), or even on unicellular organisms. There is no formalism anywhere, little effort to falsify any thesis.

What can you expect to find in this book:

  • A brief description of ALS and its common variants (PLS, PMA, etc): ~7 pages

  • A description of the cell in general, from an ALS point of view : ~15 pages

  • A strong focus on the neuronal cells, again with ALS in mind: ~34 pages

  • The main themes in ALS research (dying forward, excitotoxicity, virus, etc): ~40 pages

  • Main achievements of ALS research (SOD1, TDP-43, discovery, etc): ~113 pages

  • A focus on clinical trials and 28 drugs: ~37 pages

  • Different kind of therapies (MSC, ASO, etc): ~20 pages

  • A possible new therapy for ALS (if only a company had the will to investigate it!): ~20 pages

  • Futures therapies that are researched now (creating or grafting new neurons): ~17 pages

This is not an easy read, so I tried to explain terms, provide a large section on the neuronal cell at the beginning, and wrote 276 footnotes.

There are no speculations, nor pseudo scientific babble. I am not overly kind either with ALS scientists, clearly they can do much better.

Jean-Pierre Le Rouzic

My book on ALS research

Extracellular mitochondria and their impact on neurons

Mitochondria are frequently exchanged between cells and must change their shape accordingly to suit their environment. "Most scientists believe that mitochondria outside cells must have come from dead or dying cells," said Mochly-Rosen, who has just published an article in Nature Neuroscience. "But we found a lot of highly effective mitochondria in the culture broth, as well as some that were damaged, and the glial cells that release them seem very alive."

As recently discovered, even healthy cells regularly release mitochondria into their immediate environment.

An enzyme that destroys mitochondria

An enzyme called Drp1 that facilitates mitochondrial fission can become overactive because aggregates of neurotoxic proteins such as those associated with Alzheimer's, Parkinson's or Huntington's disease, or amyotrophic lateral sclerosis.

A fragment of protein that specifically blocks mitochondrial fission

About seven years ago, the Mochly-Rosen team designed a protein fragment, called the P110 peptide, that specifically blocks Drp1-induced mitochondrial fission when it occurs at an excessive rate, as it is the case when a cell is damaged.

Mitochondria and immune system

The relationship between mitochondria and eukaryotes has been critical to the success of metazoan life on Earth. Cellular colonization by ancestral α-proteobacteria more than a billion years ago provides benefits in terms of energy production and oxygen utilization. However, host cells needed to recognize and protect their increasingly essential endosymbioli while simultaneously identifying and repelling phylogenetically related pathogenic bacterial invaders. As a result, mitochondria have become immunologically preferred.

Nevertheless, misidentification of extracellular mitochondrial DNA, damaged mitochondria, or other damage-related molecular structures (DAMP) as a bacterium can trigger innate (sterile) immune mechanisms that in turn contribute to mitochondrial dysfunction. the spread of pathology in acute and chronic inflammatory diseases.

Loss of the immune privileged state is correlated with mitochondria damaged by microglia

Their results showed that the loss of the immune privileged state of extracellular mitochondria was correlated with an increased release of mitochondria damaged by microglia, and that the extracellular mitochondria damaged directly contributed to the spread of the disease by acting as the innate immune response by targeting adjacent astrocytes. and neurons.

An increase in Drp1 - Fis1 - mediated mitochondrial fission in activated microglia triggers the formation of fragmented and damaged mitochondria that are released from these cells, thereby inducing an innate immune response.

Fragmented mitochondria are biomarkers of neurodegeneration

Clinical and experimental studies have identified fragmented mitochondria in the biofluids of patients with subarachnoid hemorrhage and stroke patients, suggesting that their presence in the extracellular space is a biomarker of neurodegeneration and neurodegeneration. the severity of the disease. Their data showed a causal role of dysfunctional extracellular mitochondria in the propagation of neurodegenerative signals from microglia. Innate immune responses in neurodegenerative diseases begin early in the pathogenesis of these diseases and are associated with minimal, if any, infiltration of immune cells derived from blood in the brain. Resident brain cells, microglia and astrocytes, trigger this sterile immune response, contributing to neuronal dysfunction and degeneration.

P110 peptide reduces the release of damaged mitochondria from microglia

The authors have previously reported that neurons harbor neurotoxic proteins. Their data showed that the Drp1-Fis1 inhibitory peptide P110 reduces mitochondrial fission and subsequent release of damaged mitochondria from microglia, thereby inhibiting astrocyte activation and protecting neurons from innate immune attacks.

A vicious circle leads to neurodegeneration

Their data suggest instead that a relay of glie-neuron-to-glia signaling plays an important role in neurodegeneration. By fueling the vicious circle, neurotoxic protein-induced neuronal death generates additional cellular debris and debris (DAMP), as well as dysfunctional mitochondria released by microglia expressing neurotoxic proteins, exacerbate astrocyte activation. and chronic pathogenic inflammation.

Thus, neuronal cell death and the final phenotype of the disease occur via the activation of the innate immune response as well as via the direct effects of neurotoxic protein-induced cell death.

Activation of the innate immune response and neuronal protein-induced neuronal cell death in neurodegenerative disease models are both dependent on excessive Drp1-Fis1-induced mitochondrial fragmentation.

The minimal amount of damaged mitochondria required for the propagation of neuronal cell death is also unknown, and the transfer of functional mitochondria between microglia and astrocytes and between glia and neurons plays a role in physiological conditions. However, researchers know that extracellular mitochondria are essential for mediating this pathological pathology from cell to cell.

The ratio of damaged mitochondria to functional mitochondria in the extracellular medium determines the fate of neurons. Although damaged extracellular mitochondria are deleterious, functional mitochondrial transfer is protective, as previously demonstrated, for example in a murine model of acute lung injury and in a stroke model. The question of whether extracellular mitochondria damaged enter the neurons, as suggested for functional mitochondria in a previous study, has not yet been determined.

It is not the amount of extracellular mitochondria but rather the ratio of damaged mitochondria to functional mitochondria in the extracellular environment that governs the outcome of neurons and is determined by the extent of pathological fission in the microglia donor.

A slow path to developing a drug

Their data suggest that selective inhibition of pathological mitochondrial fission in microglia (mediated by Drp1 - Fis1) without affecting mitochondrial physiologic fission reduces the propagation of neuronal injury by two mechanisms

First, P110 reduced activation of the innate immune response in microglia and astrocytes and cytokine-induced neuronal cell death induced by extracellular and dysfunctional mitochondria.

Second, the inhibition of pathological mitochondrial fission by P110 in donor microglia contributed to neuronal cell survival by increasing the ratio of healthy mitochondria to damaged ones released by donor cells, thereby protecting neurons.

Suppression of DrP1 - Fis1 mediated mitochondrial fission is an easily translatable approach to interrupting this pathogenic microglia-to-astrocyte-to-neuron mitochondrial pathology, and promoting the transfer of healthy mitochondria to neurons.

However, they consider that any means of normalizing the balance between healthy and damaged mitochondria within the neuronal environment, for example by removing damaged and fragmented mitochondria with specific antibodies or by introducing healthy mitochondria, could also provide neuronal protection in neurodegenerative diseases.

Article from Nature Neuroscience: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration

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