Un essai clinique international, mais initié depuis la France cherche à savoir si la lumière infrarouge peut améliorer les symptômes de la maladie de Parkinson. Les résultats expérimentaux, basés sur des études précliniques, suggèrent en effet que l'illumination cérébrale dans le proche infrarouge est susceptible de ralentir cette maladie neurodégénérative. Hamilton, Mitrofanis et d'autres avaient précédemment rapporté que le port d'un casque équipé de LEDs infrarouges améliorait l'expression faciale, le traitement auditif, l'engagement dans la conversation, la qualité du sommeil et la motivation, bien que cela n'ait pas eu beaucoup d'effet sur les symptômes moteurs. Ann Liebert de l'Université de Sydney prévoit une étude chez 120 patients utilisant un casque plus sophistiqué.

Un système de dispositif médical (appelé Ev-NIRT) a été développé pour un éclairage intracérébral à 670 nm de la substance noire pars compacta (SNpc), et sera être testé dans cette étude pilote. Les chercheurs évalueront la faisabilité et la tolérance de la chirurgie et de l'illumination cérébrale grâce au dispositif médical Ev-NIRT, auprès d'un groupe de 7 patients atteints de la maladie de Parkinson auquels sera implanté le dispositif médical innovant. Les patients seront suivis pendant 4 ans. L'appareil émettra pendant une minute des impulsions à une longueur d'onde de 670 nm, avec une périodicité de 150 Hz. Cette salve d'impulsions sera suivie de cinq minutes de repos.

L'équipe, dirigée par le neurochirurgien Alim-Louis Benabid de l'Institut Clinatec espère que l'exposition de cette zone du cerveau à la lumière infrarouge protégera les cellules de la mort. Benabid avec Pierre Pollak, sont les pionniers qui ont développé la stimulation cérébrale profonde (DBS) en 1987. DBS fonctionne en envoyant des impulsions électriques dans le cerveau. Cette invention a changé la vie de milliers de patients, mais elle a des effects secondaires à long terme.

Il y a une dizaine d'année, John Mitrofanis, neuro-anatomiste à l'Université de Sydney, avait passé un an à étudier le DBS avec Benabid dans le but de créer un concept similaire, mais utilisant la lumière infrarouge. Mitrofanis était inspiré par les casques à infrarouge, utilisés dans la communauté Parkinson.

Benabid et Mitrofanis ont cependant estimé que la lumière provenant de l'extérieur du crâne ne pénétrerait pas assez profondément et qu'il fallait créer un dispositif implantable. En 2017, en collaboration avec la chercheuse Cécile Moro, ils ont injecté à 20 macaques une neurotoxine présente dans certaines drogues récréatives (MPTP) et connue pour provoquer les symptômes de la maladie de Parkinson. Les scientifiques ont exposés neuf macaques à du proche infrarouge dans la région du mésencéphale grâce à un dispositif implanté.

L’étude française suivra 14 patients atteints de la maladie de Parkinson à un stade précoce pendant 4 ans, dont sept seront traités périodiquement avec des impulsions de lumière de 670 nanomètres délivrées au cerveau via un mince câble à diode laser. Les sept autres patients ne seront pas opérés; un comité d'examen éthique a en effet décidé de ne pas les soumettre à une intervention chirurgicale sans possibilité de bénéfice.

Certains chercheurs sur la maladie de Parkinson sont sceptiques. Personne n'a montré pourquoi l'exposition à de l'infrarouge devrait avoir un effet sur des cellules qui ne voient jamais la lumière du jour. Les neurones n'ont pas un métabolisme basé sur la chlorophyle. Une grande partie des résultats encourageants observés jusqu'à présent peuvent être le résultat de l'effet placebo, disent les sceptiques.

Il existe trois hypothèses principales pour expliquer le fonctionnement de la photomodulation.

• La première rappelle que les molécules sensibles à la lumière du corps appelées chromophores sont excitées par stimulation photonique. On sait maintenant que l'hémoglobine, la myoglobine et la COX sont les 3 seuls chromophores dans les tissus des mammifères capables d'absorber la lumière dans le proche infrarouge (longueur d'onde de 600 à 900 nm). Cependant, il n'y a pas de mécanisme d'action clair liant ces chromophores à l'augmentation de la synthèse d'ATP qui est observée sous stimulation lumineuse.

• La deuxième hypothèse explique que la production d'énergie mitochondriale est l'effet d'une réduction de la viscosité intra-mitochondriale de l'eau induite par le proche infrarouge. la réduction de la viscosité à médiation proche infrarouge diminue le frottement qui s'oppose à la rotation de l'ATP synthase et entraîne une rotation «plus douce» de la machinerie de l'ATP synthase. Cette théorie est étayée par le fait que les augmentations du niveau d'ATP cellulaire sont immédiates après la stimulation au proche infrarouge.

• Un troisième hypothese suggére que le métabolite photo-absorbant pyrophéophorbide-a (P-a) du chlorophyl alimentaire pourrait faciliter les processus de production d'énergie par la lumière chez les animaux. Dans les expériences, les niveaux d'ATP n'ont augmenté que dans les groupes où P-a et la lumière proche infrarouge étaient co-administrés, et non dans ceux dans lesquels P-a ou proche infrarouge étaient administrés isolément. Compte tenu de la multiplicité de ces théories concurrentes, il se peut que le proche infrarouge exerce ses effets modulateurs à travers plusieurs mécanismes au lieu d'un seul.

L'objectif principal de cette nouvelle étude clinique est de prouver que l'implant est sûr, dit Benabid, mais les chercheurs évalueront également la progression de la maladie. «Cela doit induire une grande amélioration», dit-il. «Il n'y aurait aucune raison de faire une intervention chirurgicale étendue pour une amélioration qui ne serait que légère.»

Le problème majeur de tous les essais de neuroprotection dans la maladie de Parkinson est que le diagnostic semble se produire après la disparition de plus de 50% des cellules productrices de dopamine. À moins que l'amélioration ne soit énorme, le signal sera trop faible pour être détecté.

L'équipe recherchera également des avantages cliniques. Mais comme les chercheurs évaluent les symptômes de la maladie de Parkinson en observant les patients effectuant des tâches spécifiques, les évaluations sont largement subjectives et les symptômes varient dans le temps; tout le monde a de bons et de mauvais jours. Étant donné que le groupe témoin ne subira pas de chirurgie, il sera particulièrement difficile d'exclure les effets placebo.

Amyotrophic lateral sclerosis is a non-cell autonomous disease, and motor neuron degeneration is modulated by intracellular and intercellular damages. Or at least this is what tells some scientists, indeed there is an abundance of proposal for ALS etiology and no consensus.

Another dissension point between ALS scientists is if the disease starts in the brain, or in a muscle. The former is the mainstream hypothesis. Both camps have proven again and again that their proposal was the right one.

A third mystery is that scientists almost never bothered to explore the most obvious manifestation of ALS: The muscle wasting.

With the amelioration of tools' performance, scientist's attention is turning to extra cellular vesicles.

Extra cellular vesicles

In the Central Nervous System (CNS), intercellular crosstalk happens among neurons, between neurons and glia or cells of the innate immune system, through different modalities, involving the release into the extracellular space of molecules such as neurotransmitters, neurotrophic factors, metabolites, and mutant proteins encapsulated or not in vesicles.

C9orf72, which presents aberrant hexanucleotide (GGGGCC) expansion in the non-coding region in ALS patients, regulates vesicle trafficking. Other proteins such as SOD1, TDP-43 or FUS are found in vesicles in ALS.

Where we discuss of muscles

Although much less studied than for motor neurons, abnormalities have been also described in skeletal muscle from ALS patients.

Accumulation of misfolded mutant proteins is observed in skeletal muscle.

In line with the pivotal role of defective mitochondrial respiratory chain and oxidative stress in ALS skeletal muscle, increasing levels of PGC‐1α, a transcription coactivator that promotes mitochondrial biogenesis, can improve muscle function even at late stages of the disease.

Skeletal muscle is a major site of glucose storage in the form of glycogen, which is transformed into ATP through glycolysis. The dysfunction of fast‐twitch type IIb myofibres in ALS is consistent with glucose intolerance and insulin resistance reported in ALS patients.

Myofibres from transgenic mice over expressing wild‐type TDP‐43 show impaired insulin‐mediated glucose uptake.

Does muscles kill motor neurons? In ALS, muscles are supposed to die from inactivity as motor neurons do not anymore activate them. A publication on MedRxiv proposes that it is actually the other way round: Muscles kill motor neurons. After all it is well known that many ALS patients were having intense sport activities. And an ALS-like phenotype was observed in mice when exogenous human mutant SOD1 expression was restricted to the skeletal muscle.

The authors of the pre-print, Laura Le Gall, Stephanie Duguez, Pierre Francois Pradat and colleagues, recall that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. So they hypothesized that muscle vesicles may be involved in ALS pathology.

An accumulation of multivesicular bodies was observed in muscle biopsies of 27 sporadic ALS patients.

Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing.

Compared to vesicles from healthy control myotubes, when administered to healthy motor neurons the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins.

This article may revolutionize the understanding of ALS' etiology.

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

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

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

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

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

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

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

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

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

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

It was found in 2009 that toxicity of SOD1 is secondary to a gain of toxic function rather than a loss of enzymatic function of the SOD1 enzyme, thus reducing levels of the mutant protein was predicted to slow progression in SOD1-linked ALS. Tofersen (formerly known as BIIB067), is an antisense oligonucleotide designed for adults with a confirmed superoxide dismutase 1 (SOD1) genetic mutation, a subtype of familial ALS that makes up 2 percent of all ALS cases. 

As reducing levels of the mutant protein is predicted to slow progression in SOD1-linked ALS, this antisense oligonucleotide mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA. As there is less SOD1 mRNA, there is less production of the SOD1 protein. This is not without risks in itself, SOD1’s role is to protect against anti-oxidants which are the normal by-product of cellular respiration.

Tofersen was developed in a long time partnership between Biogen and Ionis Pharmaceuticals.  With the time doses went from 3mg up to 100mg. They conducted a phase 1-2 ascending-dose trial evaluating Tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of Tofersen or placebo, administered intrathecally for 12 weeks.  The results were presented in July 2020.

The results were encouraging, but as for any ALS trial they are anything but stellar. Lumbar puncture-related adverse events were observed in most participants. Among participants who received Tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52.

48 participants received all five planned doses. The technical indicators where better for participants having the higher doses. Patients taking the highest dose of Tofersen saw their ALS Functional Rating Scale score decrease by an average of 1.2 points, while the placebo group saw their score decrease by an average of 5.63 points.

Toby Ferguson the principal investigator acknowledged: “What we saw is a decline in ALS function, breathing and strength that was much greater in the placebo groups than in the treated groups. That said, if I were critical, I could poke holes in any one piece of those data, but we also have the data that SOD1 is being reduced.”

ALS is a difficult field in which drugs that show early promise can turn out to offer no benefit, or pose “unjustified risks” to patients in later studies. Biogen knows this as well as anyone, having seen its last ALS effort, dexpramipexole, fail in phase 3. Since then, the company has switched its focus from drugs with specific mechanisms, like anti-inflammatories, to medicines that target genetic mutations. Biogen strategy is  to learn more about the biology of the disease from looking at genetically defined populations (SOD1, C9orf72, ATXN2, XPO1) and then apply those findings to the broader population.

Despite those mixed results and as for other ALS drugs (Nurown, Cu(II)ATSM, Masitinib, AMX0035), there is an online petition for a compassionate access. Nearly 70,000 people have signed this online petition asking Biogen to provide an experimental ALS drug to a patient requesting it under compassionate use, but Biogen disagrees.

At the heart of Biogen’s denial is the question of broader access. The fastest way to get Tofersen to as many patients as possible would be regulatory approval, wrote Biogen chief medical officer, Maha Radhakrishnan, M.D., in a March 17 letter to an ALS patient, Stockman Mauriello that she shared with WCNC. That, of course, requires the completion of clinical trials.

“Providing individual access to Tofersen at this time could jeopardize access to Tofersen for hundreds of SOD1-ALS patients by impeding our ability to complete the study that will determine whether Tofersen is efficacious and safe and to seek subsequent regulatory approvals as quickly as possible,” Radhakrishnan wrote.

It's a moral position, it would not be fair to study participants who were randomized to placebo if Biogen were to offer the drug to patients not participating in the study.

However Biogen will provide early access to Tofersen only after study participants are no longer taking placebo.

“We cannot overlook these patients when considering questions of broader access, and cannot keep them on placebo while at the same time offering Tofersen to those outside of our study,” Sandrock wrote. “Offering Tofersen outside of the study would risk failing to complete the study and risk failing to obtain access for all SOD1-ALS patients".

“These patients agreed to participate in our study acknowledging the risk that they may not receive Tofersen, and with hope that Tofersen could be shown to work and be approved for all patients,” Sandrock wrote.

It has been clear for a while that anti-amyloid antibodies can sweep plaque from the brain, but until now the question of whether this slows cognitive decline has remained hotly contended. Despite some positive signals from four such antibodies, the data have been messy and hard to interpret.

In a Phase 2 trial, donanemab completely cleared plaque in two-thirds of participants. At the 15th International Conference on Alzheimer’s and Parkinson’s Diseases, held virtually March 10–14, Mark Mintun of Eli Lilly & Company presented the Phase 2 trial of the company’s anti-amyloid antibody donanemab.

This is the first anti-amyloid AD drug to meet a clinical endpoint in a Phase 2 trial.  While the drug met its primary endpoint, participants did not get better. Even so, donanemab slowed their decline by an average of 32 percent on a combined cognitive and functional measure. The treatment appeared to nudge down tangles, and worked best at low tangle loads.

The donanemab Phase 2 study offers some of the most compelling evidence to date that amyloid reduction can slow clinical decline, albeit modestly, in early stages of AD. In addition to the encouraging results, there are two unique features of this trial that move the field forward.

First is the decision by design to reduce dose or switch to placebo once patients are in the amyloid-negative range on PET. The discontinued dosing once the participant’s amyloid level normalizes may suggest that, if replicated, there will be not need to treat patients continuously. Doctors may be able to lower their patients amyloid levels, monitor them and, if the levels rise, re-dose. 

The second decision is the selection of patients with intermediate tau aggregates on PET. It is interesting that the overall clinical benefit was driven by the patients in the lowest tau PET tertile. This suggests that the primary role of amyloid-lowering therapies may be in patients in whom tau is not yet widespread, most of whom will be in the preclinical or very earliest clinical stage.

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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.

Research on cell lines is often the tell-tell sign of low resources combined with great ambitions. Usually this does not give good results. A recent article on the excellent eLife magazine provide a brilliant counter example to the above thesis.

Magda Luciana Atilano and her colleagues from University College London and Max Planck Institute for Biology of Ageing show that modulating insulin signaling in mammalian cells lowers C9orf72 repeat expansion.

This might seems unlikely as insulin is involved in cell’s metabolism while C9orf72 regulate endosomal trafficking and autophagy in neuronal cells and primary neurons. Those two unrelated topics at first glance.

However C9orf72 regulates GTPase such as the Rag GTPases that simulate mTORC1 and so regulate macro-autophagy. Intuitively one can imagine that increased autophagy could remedy to C9orf72 repeats, yet how C9orf72 toxic proteins are isolated and eliminated by autophagy is not known.

The authors further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR.  They found that levels of poly-GR were reduced when components of the insulin/Igf signaling pathway was genetically activated in diseased flies, suggesting a mechanism of rescue. Modulating insulin signaling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats.

Overall, the scientist’s work suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

However caution must be exercised: Flies are not humans. In invertebrates, the intracellular insulin-like signaling (ILS) pathway is regulated by multiple peptides, known as insulin-like peptides. In mammals, the ILS pathway is mediated through the binding of IGF-1 to the human IGF-1 receptor (IGF-1R) in the plasma membrane. So it remains to see how those findings would translate in humans.

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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.

Parkinson's disease is a common neurodegenerative disease. Although the exact etiology and natural course of this disease have yet to be fully clarified, numerous system-level processes and dysfunctions, have been implicated in the pathogenesis of Parkinson's disease.

Lipid droplets are highly dynamic organelles that emerge from the endoplasmic reticulum (ER) membrane. lipid droplets is involved in fatty acid storage and participate in many diseases. For example, myeloid cells, including macrophages, leukocytes, and eosinophils, form lipid droplets in response to inflammation and stress.

Normally, intracellular lipid droplets are degraded in lysosomes and deliver fatty acids to mitochondria for their consumption as an alternative energy source during periods of nutrient depletion. However, neurons have a low capacity for mitochondrial fatty acid consumption for energy production. This characteristic makes neurons particularly sensitive to lipid droplet accumulation and peroxidation.

Furthermore, the accumulation of lipid droplets enhances the fatty acid oxidation rate and imposes persistent pressure on the mitochondrial electron transport chain. Lipid overload also leads to ROS production by oxidative enzymes. Emerging evidence indicates that unexpected lipid droplet deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases.

In a previous study, Xiaojuan Han and colleagues found that kaempferol, a natural flavonoid small molecule, exhibited neuroprotective effects on mice with drug-induced Parkinson's disease.

In the current study, the authors showed in-vitro that kaempferol protected against tyrosine hydroxylase neuronal loss and behavioral deficits in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson disease mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta.

Kaempferol-rich food has been linked to a decrease in the risk of developing some types of cancers and cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables.

Kaempferol is a chemical produced by Kaempferia galanga, one of four plants called galangal. The extract of Kaempferia galanga causes central nervous system depression, a decrease in motor activity, and a decrease in respiratory rate.

The mice were treated with kaempferol. The rotarod performance time was markedly reduced in MPTP-treated mice, and this effect was prevented by kaempferol. kaempferol also restored the behavioral deficits induced by MPTP, as indicated by the reductions in the turning time and total time in the pole test, without affecting the body weights of the mice.

MPP+, the active metabolite of MPTP, inhibits mitochondrial complex enzymes and causes the cell death that is directly associated with PD. In cultured neuronal cells, kaempferol exhibited a relatively safe concentration range and significantly suppressed lipid droplet accumulation and cellular apoptosis induced by MPP.

Further studies indicated that the protective effect of kaempferol was dependent on autophagy, specifically lipophagy. Critically, kaempferol promoted autophagy to mediate lipid droplet degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death.

Furthermore a genetic knockdown abolished the neuroprotective effects of kaempferol against lipid oxidation in Parkinson disease mice.

This work demonstrates that kaempferol prevents dopaminergic neuronal degeneration in Parkinson disease via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for Parkinson disease and related NDDs.

A new article by Qaisar, Qayum and Muhammad made me think about links between severe forms of asthma and some ALS forms. Indeed this has already been questioned by scientists. There are only a few studies addressing skeletal muscle function in patients with moderate to severe asthma.

Asthma is the result of chronic inflammation of the conducting zone of the airways (most especially the bronchi and bronchioles), which subsequently results in increased contractability of the surrounding smooth muscles. This among other factors leads to bouts of narrowing of the airway and the classic symptoms of wheezing. The narrowing is typically reversible with or without treatment. Occasionally the airways themselves change.

Patients with asthma have diminished activity patterns, leading to deleterious physiologic alterations and ultimately impaired functional capacity. Moreover, they may use corticosteroids during periods of disease exacerbation.

Yet patients with asthma who use systemic corticosteroids present a decrease in respiratory muscle strength. The use of high doses of glucocorticoids causes atrophy and loss of muscle strength, a condition known as steroid myopathy.

An effective pharmacological intervention in asthma remains elusive, partly because molecular mechanisms dictating muscle decline in asthma are not known.

The authors of this new article about the relation between asthma and muscle wasting, investigated the potential contribution of skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA) to muscle atrophy and weakness in asthmatic patients.

SERCA resides in the sarcoplasmic reticulum within myocytes. The sarcoplasmic reticulum is a membrane-bound structure found within muscle cells that is similar to the endoplasmic reticulum in other cells. The main function of the sarcoplasmic reticulum is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell.[

SERCA transfers Ca2+ from the cytosol of the cell to the lumen of the sarcoplasmic reticulum. This uses energy from ATP hydrolysis during muscle relaxation.In addition to its calcium-transporting functions, SERCA also generates heat in brown adipose tissue and in skeletal muscles

Quadriceps muscle biopsies were taken from 58 to 72 years old male patients with mild and advanced asthma and the SERCA activity was analyzed in association with cellular redox environment and myonuclear domain size.

Maximal SERCA activity was reduced in skeletal muscles of mild and advanced asthmatics and was associated with reduced expression of SERCA protein and upregulation of sarcolipin, a SERCA inhibitory lipoprotein.

Sarcolipin is an important mediator of muscle based non shivering thermogenesis. It causes the sarcoplasmic reticulum Ca2+-ATPases to stop pumping Ca2+ ions but continue futilely hydrolysing ATP, thus releasing the energy as heat. Sarcolipin mediated heat production is very important for many organisms to maintain a warm body. In mammals thermogenesis by skeletal muscles is complemented by thermogenesis in the brown adipose tissue.

The authors also found downregulation of Ca2+ release protein calstabin and upregulation of Ca2+ buffer, calsequestrin in skeletal muscles of asthmatic patients. The atrophic single muscle fibers had smaller cytoplasmic domains per myonucleus possibly indicating the reduced transcriptional reserves of individual myonuclei. Plasma periostin and C-terminal Agrin Fragment 22 (CAF22) levels were significantly elevated in asthmatic patients and showed a strong correlation with hand-grip strength. These changes were accompanied by substantially elevated markers of global oxidative stress including lipid peroxidation and mitochondrial ROS production.

Agrin, a synaptically located protein, is a key player during initial formation and maintenance of neuromuscularjunctions (NMJ). During development, nerve cells approach muscle fibers and establish synaptic contacts defined as NMJ. Initially, the NMJ is small and weak, but if the contact is successful the connection is maintained and reinforced. Agrin induces and stabilizes clusters of AChRs at the NMJ, promotes synaptic maturation, and maintains the mature state of the NMJ.

C-terminal Agrin Fragment has been proposed as a novel biomarker for sarcopenia originating from the degeneration of the neuromuscular junctions. Manipulation of the agrin signaling path may therefore be a promising way to correct neuromuscular defects.

During development in humans, the growing end of motor neuron axons secrete agrin. When secreted, agrin binds to several receptors on the surface of skeletal muscle. The receptor which appears to be required for the formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle specific kinase). Elevation of MuSK signaling has improved motor performance and delayed denervation in ALS mice (Perez-Garcia and Burden, 2012).

Taken together, the scientists' data suggest that muscle weakness and atrophy in asthma is in part driven by SERCA dysfunction and oxidative stress. The data propose SERCA dysfunction as a therapeutic intervention to address muscle decline in asthma.

You can write me at contact at padiracinnovation.org

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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.