Free amino acids in motor cortex of amyotrophic lateral sclerosis

Summary Free amino acids were estimated quantitatively in the motor cortex from 3 patients with amyotrophic lateral sclerosis (ALS) and 11 control subjects. Among 7 amino acids which showed statistically significant changes, taurine was the only one which was increased constantly and most markedly in the motor cortex of all the 3 ALS cases. It was suggested that the metabolism of sulfur amino acids might be affected in comparatively early stages of ALS.Acknowledgments. The authors are grateful to Dr M. Uono, Department of Neurology, Tokyo Metropolitan Hospital of Fuchu, and Dr K. Hirayama, Department of Neurology, Brain Research Institute, School of Medicine, Chiba University, for their generous cooperation.     

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression.     

Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis

Five structurally and functionally different proteins, an enzyme superoxide dismutase 1 (SOD1), a TAR-DNA binding protein-43 (TDP-43), an RNA-binding protein FUS, a cofilin-binding protein C9orf72, and polypeptides generated as a result of its intronic hexanucleotide expansions, and to lesser degree actin-binding profilin-1 (PFN1), are considered to be the major drivers of amyotrophic lateral sclerosis. One of the features common to these proteins is the presence of significant levels of intrinsic disorder. The goal of this study is to consider these neurodegeneration-related proteins from the intrinsic disorder perspective. To this end, we employed a broad set of computational tools for intrinsic disorder analysis and conducted intensive literature search to gain information on the structural peculiarities of SOD1, TDP-43, FUS, C9orf72, and PFN1 and their intrinsic disorder predispositions, and the roles of intrinsic disorder in their normal and pathological functions.     

Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis

Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.     

The multifaceted role of glial cells in amyotrophic lateral sclerosis

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.     

Free amino acids inLimnaea II

Résumé De nouvelles recherches ont amené les auteurs à constater l'existence de seulement 2 ou 3 acides aminés dans les ufs de la Limnée (Gastéropode), un jour avant l'éclosion. Ces acides sont très semblables à ceux que l'on trouve chez les jeunes escargots. Dans les produits hydrolytiques des protéines de l'escargot adulte, on constate la présence de 9 acides aminés.     

Free amino acids inLimnaea III

Résumé L'auteur a constaté que les acides aminés libres chez les gastéropodes du genreLimnaea, immédiatement après l'éclosion, sont les mêmes que chez les adultes. Il a essayé aussi d'identifier chez des sujets adultes les quatre acides-aminés libres les plus caractéristiques. Deux d'entr'eux sont probablement l'acide glutamique et la sérine.     

Free amino acids in some tissues of marine crustacea

Summary Free amino acids contained in extracts of crustaceans were separated and determined quantitatively by ion exchange chromatography. In the hepatoprancreas of the brachyuran crustaceanCarcinus maenas, glycine, arginine, proline and alanine constituted 78.7% of the total amino acid pool. InEriphia spinifrons andMaja verrucosa, glycine, alanine, lysine and leucine comprised 54.9–66.9% of the total content. In the muscle tissue of the macruran crustaceaPalaemon, glycine, arginine, proline and alanine were the most common free amino acids and comprised 70–95% of the total content. The high concentrations of some amino acids in tissues of crustaceans may play a role in intracellular osmotic regulation and also in the maintenance of ionic hydrogen concentration.Acknowledgments. The author wishes to thank Mr R. Mari for his skillful help in the amino acid analyses and Miss G. Princivalli for typing the mansucript.     

Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches for ALS, considering what has been done and the possible future directions for effective application of the latest generation of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical progress in treating ALS.     

Free amino acids in the egg fluid and embryos ofPila

Résumé Dans la capsule des ufs dePila (Gastéropode), le fluide alimentaire contient à peu près tous les acides-aminés libres qui existent aussi dans l'embryon bien développé. L'auteur a déterminé le nombre des acidesaminés libres qui se trouvent dans le corps de ces escargots après l'éclosion. Le modèle-type des acides-aminés libres reste inchangé chez les individus affamés.     

Free amino acids of the hemolymph ofAnacridum aegyptium L. (orthoptera)

Riassunto Sono stati determinati 14 aminoacidi liberi nell'emolinfa: di cssi acido glutamico, glicina e prolina rappresentano insieme il 50% e più del contenuto totale. Le ninfe verdi contengono meno glicina e acido aspartico e più treonina e fenilalanina in confronto alle ninfe brune. Gli individui adulti mostrano in contenuto relativo di aminoacidi diverso dalle ninfe e fra i due sessi. Somministrazione di triptofano a ninfe brune non ha dato variazioni negli aminoacidi liberi, non aumento dell'aminoacido stesso, né presenza di prodotti del suo metabolismo nel sangue.     

Free amino acids in the haemolymph ofEoperipatur weldoni (onychophora)

Zusammenfassung Mit der Methodk nach Folin und Spackmann wurden die Freien Aminosäuren in der Hämolymphe vonEoperipatus weldoni festgestellt und in ihrer Gesamtkonzentration mit den Aminosären der Myriapoden und primitiven hemimetabolischen Insekten vergleichbar gefunden.

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Acknowledgments. We thank Mr.Manmohan Singh of Batu Satu, Malaysia, for the collection of animals used in this study. We are grateful to Dr.G. Krishnan for helpful crticism.     

Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3–5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.     

Determination of cerebrospinal fluid and serum lead levels in patients with amyotrophic lateral sclerosis and other neurological diseases

In a total of 62 samples of cerebrospinal fluid (CSF) and an equal number of serum samples obtained from 16 patients suffering from amyotrophic lateral sclerosis, 22 patients suffering from miscellaneous neurological diseases, and 24 controls, lead was measured by atomic absorption spectrophotometry. No statistical difference in lead concentration was found between the above three groups.     

Free amino acids in blood serum of hedgehogs in deep hypothermia and after spontaneous arousals

Zusammenfassung Die Serumkonzentration von 21 freien Aminosäuren wurde bei Igeln im Winterschlaf, bei spontanem Erwachen während des Winterschlafs und nach dem Aufwachen im Frühling bestimmt. Mit Ausnahme von Valin, Leucin, Isoleucin und Tryptophan sinken die Aminosäuren während des Schlafes signifikant ab und steigen beim Erwachen im Winter und Frühling an.

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This work was supported by a grant from the National Research Council for Sciences.     

Free amino acids in the testes ofGryllotalpa africana beauvois (Orthoptera,Gryllidae)

Zusammenfassung Zweidimensionale Chromatographie der Hoden vonG. africana ergibt das Vorkommen von elf Aminosäuren: Leucin (Isoleucin), Valin, Prolin, Tyrosin, Alanin, Glycin, Serin, Glutaminsäure und Asparaginsäure. Höchste Konzentration fand sich bei Prolin und Asparaginsäure, niedrigste bei Serin und Tyrosin.     

Free amino acids in the adult citrus brown mite,Eutetranychus orientalis (Klein)

Summary Amino acids contained in extracts of adultEutetranychus orientalis were separated and determined quantitatively by 2-dimensional paper chromatography. 14 amino acids were identified. Asparagine, ornithine, histidine, lysine, aspartic acid, serine and glycine were the major components of the free amino acid pool, comprising 83.94% of the total content.