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You remember that in 2016, a group of scientists of Case Western Reserve University, Cleveland, found that in ALS, TDP-43 is mislocated in the mitochondria. TDP-43 is a protein which is involved in 95% of ALS cases, 1/3 of Alzheimer cases and in several other neurodegenerative diseases.

But not all neurodegenerative diseases are TDP-43 proteopathies, for example Parkinson is mainly a α-synuclein proteopathy. In Parkinson the intracellular inclusions, that contain aggregates of the intrinsically disordered protein α-synuclein, are called Lewy bodies.

Now a group of scientists in Switzerland and Sweden, have found that if the action of some chaperones (molecules that process proteins, including for protein folding) is impaired, then α-synuclein tended to accumulate in the mitochondria where it aggregated, forming clumps of protein that bear a striking resemblance to Lewy bodies.

The reseachers found that six highly divergent molecular chaperones commonly recognize a canonical motif in α-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of α-synuclein.

Specific inhibition of the interactions between α-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90β, results in transient membrane binding and triggers a remarkable re-localization of α-synuclein to the mitochondria and concomitant formation of aggregates.

Phosphorylation of α-synuclein at Tyr39 directly impairs the interaction of α-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson’s disease. One mechanism that was invoked in Parkinson is apoptotic pathway activation via Abelson (c-Abl), so Tyrosine kinase inhibitors were envisaged to treat Parkinson. This mirrors their usage to treat ALS.

The results of the European scientists establish a master regulatory mechanism of α-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson’s disease.

If we return to ALS and the Case Western scientists, they similarly thought that chaperones were involved in the mislocalisation of TDP-43 in mitochondria:

Considering that molecular chaperones are usually needed to unfold protein before and during import 22 , perhaps the final localization of TDP-43 in mitochondria depends on multiple factors, including, but not limited to, TOM and TIM22 complexes, ∆ψ and chaperones.

The article about α-synuclein : https://www.nature.com/articles/s41586-019-1808-9

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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.

Blood-brain barrier (BBB) ​​dysfunction is increasingly emerging as an early and important mechanism that may underlie some of the cognitive changes seen in the aging process and in the development of neurodegenerative diseases, including including Alzheimer's disease.

enter image description here Source: Ben Brahim Mohammed, wikimedia.org/w/index.php?curid=12263975

A common denominator in studies on this subject is that the dysfunctional blood-brain barrier releases toxic products derived from blood in the brain, such as fibrinogen, thrombin, plasminogen, iron-containing proteins, albumin, etc., which disrupt normal neuronal function, possibly leading to neuronal and synaptic loss and/or cognitive decline in Alzheimer's disease.

In a series of experiments on mice and humans, Senatorov et al. show that BBB dysfunction occurs with aging and leads to hyperactivation of TGFβ signaling in astrocytes, which in turn leads to dysfunction of the neural network, particularly in the hippocampus. These dysfunctions could be corrected by intraperitoneal infusions of a small molecule TGFβR1 kinase inhibitor (IPW).

In a separate but related study, Milikovsky et al. show a link between electrographic anomalies - paroxysmal slow wave events (PSWE) - detected using EEG, and cognitive disorders. They show that PSWE are observed in a number of human and murine models of blood-brain barrier dysfunction, and that PSWE can be induced by exposing the mouse brain to albumin.

These two studies provide convincing evidence for a causal link between a deficiency of the blood-brain barrier and neuronal dysfunction. They suggest that this interaction may be mediated by specific astrocytic pathways, leading to electrographic dysfunction that can be quantified using EEG, and especially suggest that this pathological pathway may be a treatable therapeutic target.

Further studies are needed to determine the extent to which protein infusion (Aβ, tau, α-synuclein, TDP43) in the central nervous system contributes to the cognitive changes observed in aging and neurodegenerative diseases in humans, and what strategies to block astrocyte TGFβ signaling (eg using IPW or losartan) are feasible, safe and therapeutically useful for patients.

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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.

Placental invasion into the maternal endometrium of the uterus has substantial similarities with the early spread of cancer in the stroma (the part of a tissue or organ with a structural or connective role). These similarities have inspired the hypothesis that trophoblasts (the continuous cell layer of fibroblasts that limit the egg, which became blastocyst at day 6 after fertilization) have developed the ability to invade the endometrium, leading to invasive placentation. Invasion of a specific type of trophoblast (extravillous trophoblast) in the maternal uterus is a vital step in the establishment of pregnancy. * Zephyris Source CC BY-SA 3.0, * https://commons.wikimedia.org/w/index.php?curid=10811330

These mechanisms can be reactivated in cancer cells, leading to a predisposition to metastasis. It had been hypothesized (the ELI hypothesis) that cancer malignancy should be limited to placental mammals where invasive placentation first evolved. But there are several counterexamples.

In a recent article, the authors explore an alternative scenario in which stromal cells of the uterus evolved to resist or allow invasion, determining the outcome of placental invasiveness. The likelihood that changes in the stromal environment will lead to changes in cancer malignancy is reinforced by the fact that the molecular mechanisms used by cancer cells to metastasize are shared with other biological processes.

For example, mechanisms regulating gastrulation, wound healing, leukocyte extravasation, etc., are shared with both trophoblast and cancer invasion. This implies that invasive cancer cells use mechanisms that have evolved much earlier than placental invasion and, therefore, the evolution of invasive placentation per se can not be responsible for the origin of malignant cancer.

It is important to note, however, that the invasive nature of the placenta continued to evolve after its origin. Mammalian species differ in their tumorigenesis potential, as well as their vulnerability to cancer metastasis.

While the evolution resulted in an even higher degree of invasiveness in great apes, which includes humans, a complete loss of placental invasion has evolved in hoofed mammals, such as cows and horses and their parents, and these animals have lower malignancy rates for a variety of cancers.

In a recent review, Constanzo et al. presented compelling arguments for a model in which cancer progression in humans includes reactivation of the expression of embryonic genes normally controlling placental development and the development of the placenta. immune evasion.

For example, melanoma occurs in cattle and equines but remains largely benign; while it is very malign in the human. This correlates with the phenotype of the fetal-maternal interface (the degree of placental invasion during pregnancy). In particular, these results support that TGF-β secretion and high non-canonical WNT signaling in stromal cells are causal factors accounting for the high vulnerability of human stromal tissues to cancer invasion, at least in the case of melanoma .

Their data support the ELI hypothesis, suggesting that differences in stromal gene expression between species are critical in determining the degree of embryo implantation as well as stromal resistance to early cancer dissemination.

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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.

Senescent cells feed on neighboring cells

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Cells that are damaged or dysfunctional and pose a threat are either eliminated by cell death or undergo a generally irreversible state called senescence. Senescent cells usually do not divide, but they can persist in tissues and contribute to aging and cancer. Senescent cells often become larger and may have higher energy requirements than healthy cells.

In the "Journal of Cell Biology", Tonnessen-Murray and colleagues describe an activity that underlies the persistence of senescent cells - they can find extra energy by cannibalizing neighboring cells.

enter image description here

Chemotherapy that damages the DNA of cancer cells can lead cells to death or senescence. Cellular entry into senescence benefits an organism by inhibiting the development of cancer by preventing the division of cells that have accumulated significant DNA damage.

Tonnessen-Murray and colleagues investigated the effects of chemotherapy-induced senescence in breast cancer cells in mice treated with doxorubicin, a chemotherapeutic drug.

These senescent cells absorb and digest neighboring living cells. The cells are engulfed by a process that has the molecular characteristics of phagocytosis, a process used by immune cells. Once ingested, the cells are enveloped in the membrane of an organelle called lysosome and digested.

This degradation provides metabolic building blocks for the cell. Senescent cells that have ingested their neighbors survive longer than senescent cells that have not. This suggests that the metabolic building blocks recovered from lysosomal digestion of neighboring cells were used by senescent cells to promote their survival.

This surprising discovery highlights the complexity of the regulation of cell death in multicellular animals. Many mechanisms of cell death occur in animal tissues. These include forms of cell suicide, such as apoptosis, which leads to fragmentation of individual cells, and regulated forms of necrotic cell death that cause cell disruption. Some cases of engulfing cells occur through at least two distinct mechanisms:

  • One is a form of cell suicide called entosis, in which cells invade a neighboring cell and are phagocytized by it.
  • The other mechanism is cellular cannibalism resembling the process used by immune system cells such as macrophages to ingest and destroy dying cells.

The authors analyzed the gene expression profile of cancer cells treated with chemotherapy drugs (most of these cells were senescent) and found that the characteristic genes for phagocytosis were expressed. This gene expression culminated in a time that correlated with cell engulfment. They also observed that senescent cells engulfed dead cells added in vitro, providing a further clue that senescent cells engulf cells by phagocytosis.

Cellular cannibalism in cancers has already been reported. However, Tonnessen-Murray and his colleagues specifically identified an association between cannibalism and senescence, and they show that this phenomenon could make a substantial contribution to the persistence of senescent cells in cancerous tissues. Their results suggest that cellular cannibalism may be an activity that is largely associated with the induction of senescence, rather than being related to particular types of cancer or the status of proteins such as p53. It will be important to study if cannibalism is related to senescence in other contexts, for example the proteopathies that are found in neurodegenerative diseases, which moreover was suggested more than 10 years ago by Todd E Golde, and Victor M Miller. Since 2018, it has been known that senescent astrocytes and microglia accumulate in the brain in the context of diseases associated with Tau protein.

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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.

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.

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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.

Tau proteins stabilize the microtubules ensuring the shape of the cell. They are abundant in neurons of the central nervous system and less common elsewhere. Nervous system pathologies and dementias as Alzheimer's disease and Parkinson's disease are associated with Tau proteins become defective and do not properly stabilize microtubules.

enter image description here

In an article published November 19, 2019 in the Journal of Alzheimer's Disease titled "* In vivo Validation of a Small Molecule Inhibitor of Tau's Self-association in Mouse * *", there is a small molecule inhibited by the self-associated Tau protein in the hippocampus of a murine model of tauopathy that expresses the six isoforms of the human Tau protein.

Oligomers have played a role in the progression of Alzheimer's disease and related tauopathies. Tau transmitted the pathology to diseased neurons, through the process of Tau gene replication and aggregation.

In order to develop a small therapeutic molecule for Alzheimer's disease and associated tauopathies, Davidowitz and other researchers then developed in vitro and cellular assays to make inhibitory molecules the first step in aggregating Tau protein. , the self-association of the Tau protein in oligomers.

In vivo validation studies of a major compound were performed in the murine model of tauopathy and which express the human isoforms of Tau. The treated mice showed no adverse event related to the administration of the molecule.

Tau auto-Associated and Aggregates Totals and Phosphorylates of Tau insoluble. The dose response was linear with respect to compound levels in the brain.

A study to confirm with a mouse mouse. The results were tested during the targeting process of self-association by in vitro and cellular assays on an in vivo model of Tau aggregation.

"This study validates the waterfall of the waterfall at the beginning of the cascade of aggregation.", Commented James Moe, Ph.D., MBA, President and CEO of Oligomerix, and one of the authors of the publication.

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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 forms of DNA, in Eukariotic cells that are not in replicating phases they are long linear structures, but in mitochondria they are circular. In bacteria DNA is also circular. Plasmids, another form of DNA is also circular.

While the chromosomes are big and contain all the essential genetic information for living under normal conditions, plasmids usually are very small and contain only additional genes that may be useful in certain situations or conditions.

Plasmids are capable of replicating autonomously within a suitable host, they are transmitted from one bacterium to another (even of another species), this host-to-host transfer of genetic material is one mechanism of horizontal gene transfer

Several forms of ADN

Since the 1970' we know that plasmid like DNA exist also organisms and they are involved in cancer. ecDNAs are fragments of extrachromosomal DNA, which were originally observed in a large number of human tumors and most notably, neuroblastoma.

In contrast to bacterial plasmids or mitochondrial DNA, ecDNA are chromatinized, containing high levels of active histone marks, but a paucity of repressive histone marks. The ecDNA chromatin architecture lacks the higher-order compaction that is present on chromosomal DNA and is among the most accessible DNA in the entire cancer genome.

For their new study, Paul Mischel and colleagues shown that ecDNA are wound around protein cores in a fashion that permits a far greater level of accessibility to the transcriptional machinery than occurs on chromosomes. As a result of this unique architecture, along with the very high number of ecDNA particles inside a tumor cell, oncogenes that are amplified on ecDNA are amongst the most highly transcribed genes in a tumor. Mischel and teammates have constructed circular maps of ecDNA which they say might prove valuable in guiding drug discovery.

The study’s co-senior author, UCSD's Paul Mischel, Ph.D., has founded a biotech called Boundless Bio to advance treatments aimed at ecDNA. In September, the startup emerged from stealth mode with $46 million in series A funding led by Arch Venture Partners and City Hill Ventures.

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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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