The TCA cycle (Krebs cycle) is the primary mechanism for ATP synthesis in brain cells, operating within the mitochondria's matrix. Additionally, glycolysis contributes to ATP production, particularly during heightened energy demands or glucose scarcity. Insulin plays a crucial role in regulating glucose metabolism and maintaining neuronal function.

Mitochondria, akin to tiny microbe-like structures, are strategically located within cells to provide energy where needed, including neuronal terminals. Synthesized primarily in the soma, the central part of the neuron, mitochondria must undergo transport to distant neuronal terminals. Maintenance of mitochondrial health is crucial as damaged mitochondria can induce oxidative stress, necessitating fusion with healthy counterparts for repair or elimination. Thus, ensuring mitochondrial integrity is paramount for neuronal function.

In both processes -glycolysis and the citric acid cycle- during oxidative phosphorylation (OXPHOS) glucose and other substrates are metabolized, generating the synthesis of ATP.

A new text using the detrimental effects of S-nitrosylation on TCA cycle function, provides insights into potential therapeutic interventions.

The scientists compared in-vitro isogenic wild-type and Alzheimer's disease mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN) and found evidence of dysfunctional processes in mitochondria. This aberrant S-nitrosylation is documented not only in hiN cells but also in postmortem human Alzheimer's disease brains versus controls

Detailed analyses showed significant inhibition of metabolic flux at various steps of the TCA cycle in hiN. It suggests that deficiencies in TCA cycle function were associated with a shift towards compensatory glycolysis, suggesting an adaptive response to impaired oxidative phosphorylation. In particular, supplementation with dimethyl succinate, a substrate bypassing the inhibited step in the TCA cycle, suggests a potential therapeutic strategy to mitigate mitochondrial dysfunction in Alzheimer's disease. Dimethyl succinate (DMS), a membrane-permeant form of succinate, could serve as a pro-drug to provide substrate to the next enzymatic step in the TCA cycle, succinate dehydrogenase (SDH).

Those findings are not entirely surprising and the motivation of the scientists seems more to test a new mass spectroscopy technique than finding a drug. Anyway, it may add to the incentive to make pre-clinical trials of dimethyl succinate in rat Alzheimer's disease models.

Usually, Dimethyl succinate is sometimes used as a solvent. Yet dimethyl succinate is an irritant and an explosive product.

Unfortunately, after decades of research and hundreds of unsuccessful phase III clinical trials, it's clear that the pharmacological industry and a cohort of academic laboratories are unable to create drugs that slow significantly the progression of neurodegenerative diseases.

Some courageous scientists interrogate basic hypotheses or design longer, more complex better clinical trials. For example, Alzheimer's disease can't seriously be attributed to any molecular dysfunction, as it would mean that a lot of cerebral functions would be affected, not only memory issues, and anyway, memory issues in Alzheimer's are much more complex than described in textbooks: They did not simply vanish: The patient looks to be living today in the context of the past. Sometimes the patient can discuss simultaneously at two levels: In the context of the past (when they were infants) and in the context of today.

Others are currently busy breaking the thermometer. If the clinical diagnosis makes it impossible to validate current clinical trials, then change the way success is defined: Abandon clinical criteria and use molecular criteria. They did it recently for Alzheimer's disease and now they propose it for Parkinson's disease..

The immediate consequence will be a flurry of successful clinical trials, even if patients get no improvements, as they did for Aducanumab.

There will also be false positives, people will be diagnosed sick because of the presence of a molecule but without any clinical signs.

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

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

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

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

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

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

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

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

Quelques jours avant que mon père décède, j'ai demandé à son médecin quelles pouvaient être les actions médicales à mener pour améliorer son état. Le médecin m'a répondu "si on arrive à améliorer ses constantes, il ira mieux".

Outre le fait que le médecin ne me répondait pas vraiment en terme d'actions à mener, cette lapalissade enseigne quelque chose de fondamental au sujet de l'approche de la santé par la médecine.

Les médecins sont conscients qu'en fait ils ne peuvent peuvent pas vraiment soigner, ils ne peuvent qu'améliorer un dysfonctionnement d'un corps qui autrement doit être en bonne santé. Ce corps, si on l'aide, va retrouver sa bonne santé.

Au contraire, une personne atteinte de comorbiditées a une chance de survie très faible, c'est de la statistique élémentaire. Si un malade a trois problèmes de santé ayant chacun une chance de survie de l'ordre de 80%, la résultante n'est que de 51%. Il est donc illusoire de penser que quand la physiologie est sévèrement compromise, on pourra restituer la santé avec une pilule ou une injection miracle.

Cette limitation de la médecine actuelle, n'est pas compris par les scientifiques. Ceux-ci s'obstinent à penser qu'en agissant sur une composante infinitésimale de notre physiologie, la santé sera, comme par magie, restituée. Cet aveuglement s'explique par le fait que la quasi totalité des scientifiques oeuvrant dans la recherche médicale, n'ont qu'une notion vague de la physiologie humaine et des interactions entre ses multiples systèmes.

Cela explique pourquoi je ne présente pas les multiples articles qui apparaissent tous les jours et qui annoncent une découverte majeure, alors que le plus souvent il s'agit de travaux mineures sur une souris, ou pire encore sur une lignée de cellules dénaturées immortelles.

Outre le fait qu'un scientifique doit publier pour être crédible, et donc qu'on a une avalanche de papiers au style ampoulé mais sans valeur, beaucoup se demandent pourquoi les souris semblent si bien répondre aux traitements, alors que quand ces traitements sont testés sur des humains, ils échouent à améliorer l'état des malades.

La réponse est complexe, mais un point essentiel est celui-ci: La tenue de l'expérience est soit confiée à des étudiants (masters, doctorants), des salariés (postdocs) ou à un organisme de sous-traitance de la recherche (CRO). Dans ces différents cas de figure, les personnes à qui sont confiées ces souris ont intérêt à ce que l'hypothèse faite par le professeur donneur d'ordre soit avérée. or on sait que la santé d'une souris est fortement dépendante à des caresses ou à un nettoyage de la litière (ce qui d'ailleurs influence le microbiome intestinal)...

La moralité de tout ceci est que pour un patient il faut essayer de faire fonctionner normalement son corps et son esprit autant que possible: Conserver une certaine activité physique, conserver une activité intellectuelle, s'informer à des sources fiables, avoir une sécurité financière, combattre les problèmes cardio-vasculaires, notamment l'hypertension artérielle, et lutter contre le diabète notamment en limitant la plage horaire où l'on ingère de la nourriture, conserver des contact sociaux notamment parce que celà oblige à faire attention à soit-même, combattre le tabagisme et dormir convenablement.

Cela est plus facile à écrire qu'à mettre en oeuvre.

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

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

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

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

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

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

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

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

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

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

Alpha-synuclein, the protein implicated in Parkinson's disease, is primarily localized in presynaptic terminals of neurons. In particular, it is involved in the regulation of neurotransmitter release, maintenance of synaptic integrity, and plasticity of synapses and, consequently, cognitive processes. But it's not simply the presence of a protein that is important, much more important is the place and time a protein changes, either in location, composition, or in shape. Those changes are caused by a chemical signal for example: phosphorylation. Phosphorylation events are omnipresent in our bodies. For example, phosphorylation of muscles' myosin, enables the contraction of muscle filaments. Phosphorylation is catalyzed by enzymes known as kinases which regulate various cellular functions by adding phosphate groups to specific target molecules. The phosphorylation-dephosphorylation cycle is dynamic and reversible, providing cells with a rapid and precise means of responding to external cues. Importantly, the balance between kinase and phosphatase activity (enzymes that remove phosphate groups) determines the overall phosphorylation status of a cell and influences its physiological state.

The phosphorylation of alpha-synuclein is associated with the formation of aggregates like Lewy bodies, contributing to the neurodegenerative process characteristic of Parkinson's disease and Lewy body dementia. It is not known if the phosphorylation of alpha-synuclein is causative of Parkinson's disease and Lewy body dementia.

This addition of a phosphate group is done at specific sites in the molecules, in the case of alpha-synuclein, it is done at a site called Ser129. Previous research suggested that abnormal accumulation of alpha-synuclein, when phosphorylated at Ser129, contributes to the formation of Lewy bodies—protein aggregates commonly found in the brains of individuals with Parkinson's. These Lewy bodies are associated with the degeneration of dopaminergic neurons, a hallmark of Parkinson's disease.

A new publication by Leonardo Parra-Rivas, Subhojit Roy, and colleagues at the University of California, San Diego, investigates the phosphorylation of alpha-synuclein (α-syn) at the Ser129 site and its implications in Parkinson's disease (PD) and related synucleinopathies.

Their study challenges the view that Ser129 phosphorylation directly causes toxicity and proposes a physiologic role in synaptic function. Indeed this has consequences Their new research somehow has consequences for common statements that abnormal accumulation of phosphorylated alpha-synuclein, contributes to the formation of Lewy bodies—protein.

Almost all pathologically aggregated α-syn in Lewy bodies is phosphorylated at Ser129. Antibodies to Ser129 α-syn are sensitive markers for neuropathologic diagnosis in synucleinopathies. Studies often use Ser129 phosphorylation as a surrogate marker for pathology. Intrigually, inhibitors against Polo-like kinase 2 (PLK2), responsible for α-syn phosphorylation, were explored as a PD drug target. However, PLK2 over-expression surprisingly suppressed neurodegeneration in vivo, challenging expectations. This hints that the physiological role of phosphorylated α-syn at Ser129 is misunderstood.

For the authors of this new publication, under normal physiological conditions, only a small fraction (∼4%) of α-syn is phosphorylated at Ser129. Despite its low frequency, Ser129P is produced during normal metabolism, raising questions about its exclusive pathological role. A recent study suggests that increasing neuronal activity augments Ser129 phosphorylation, implying that it may be linked to an increase in cognitive works and that the role of α-synuclein protein may be to regulate excessive neuronal firing. This suggests that α-syn might have a role in healthy brains, which had not previously been investigated. The researchers give an interesting example: "In hindsight, we hadn't been looking at synuclein phosphorylation the right way, take, for instance, the circuits in the olfactory bulb, which according to our data has high levels of phosphorylated α-synuclein. The nose never stops smelling, so it needs to be active all the time. One hypothesis is that synuclein phosphorylation may have evolved as a safety mechanism to protect neuronal circuits that need to be hyperactive."

The authors systematically examined α-syn Ser129 phosphorylation using various assays, in vivo studies, cell-free assays, mass spectrometry, electron microscopy, and dynamic simulations. when α-synuclein is phosphorylated, its structure changes in a way that promotes interactions with other proteins in healthy brains. The scientists propose a model where Ser129 phosphorylation induces conformational changes at the α-syn C terminus, facilitating its association with functional interacting partners and eliciting α-syn function.

Conclusion: The study challenges the view that Ser129 phosphorylation directly causes toxicity and proposes a physiologic role in synaptic function. Yet it is done on cultured cells and in mouse brain tissue, so those findings are far from being confirmed in humans. As we all know you can find contradictory studies in scientific literature and only clinical trials are credible (when authorities do not bypass their findings).