Unsuspected task for an old team: Succinate, fumarate and other Krebs cycle acids in metabolic remodeling

AbstractSeventy years from the formalization of the Krebs cycle as the central metabolic turntable sustaining the cell respiratory process, key functions of several of its intermediates, especially succinate and fumarate, have been recently uncovered. The presumably immutable organization of the cycle has been challenged by a number of observations, and the variable subcellular location of a number of its constitutive protein components is now well recognized, although yet unexplained. Nonetheless, the most striking observations have been made in the recent period while investigating human diseases, especially a set of specific cancers, revealing the crucial role of Krebs cycle intermediates as factors affecting genes methylation and thus cell remodeling. We review here the recent advances and persisting incognita about the role of Krebs cycle acids in diverse aspects of cellular life and human pathology

ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly

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Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

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Study of the therapeutic potential of human embryonic stem cells for cell therapy of HD

La maladie de Huntington (MH) est une maladie neurodégénérative rare, qui affecte les neurones GABAergiques moyens épineux (MSN) du striatum. Actuellement aucun traitement ne permet de guérir cette pathologie. Un essai clinique pilote, fondé sur la greffe intracérébrale de tissus fœtaux humains, a permis de remplacer les cellules lésées et de corriger certains symptômes. Néanmoins, la logistique nécessaire pour accéder à ces cellules limite cette forme de thérapie cellulaire à un nombre de patients restreint. Il est nécessaire d’identifier une source alternative de cellules capables de remplacer efficacement les tissus fœtaux. Les cellules souches embryonnaires humaines (hES) possèdent deux propriétés essentielles, l’autorenouvellement et la pluripotence, qui en font des candidats intéressants. L’objectif de notre étude a été d’évaluer le potentiel thérapeutique de ces cellules pour la thérapie cellulaire de la MH. Nous avons élaboré un protocole permettant la production, in vitro, de progéniteurs striataux capables de se différencier en MSN, à partir de cellules hES. Une fois greffés dans un striatum lésé de rat, ces progéniteurs peuvent survivre et se différencier en neurones MSN. Ces expériences de xénogreffes ont d’autres parts révélés la présence de cellules neurales prolifératives persistantes. L’ensemble de nos résultats démontre que les cellules hES constituent une source cellulaire alternative pertinente pour la thérapie cellulaire de la MH. Cependant, ils soulignent la nécessité de mettre en place des mesures spécifiques pour contrôler la prolifération in vivo des greffons issus de cellules hES, avant d’envisager toute application clinique.Huntington’s disease (HD) is a neurodegenerative monogenic disorder resulting primarily in loss of GABAergic medium spiny striatal neurons (MSN). There is no known treatment to cure this pathology. Recent clinical trials consisting in transplanting human fetal tissue into the striatum of HD patients resulted in the substitution of lost cells and lead to functional benefits. However, application of this treatment to a large number of patients is restricted because the source and the processing of fetal cells are limiting factors. Thus, it is necessary to identify an alternative source of cells suitable to replace efficiently fetal tissue. Human embryonic stem (hES) cells, because they are self-renewable and pluripotent, are prime candidates. The aim of our work was to evaluate the therapeutic potential of hES cells for cell therapy of HD. We have designed a protocol to direct the differentiation of hES cells toward a striatal neuronal fate. This protocol allows the production from hES cells of striatal progenitors that are able to differentiate in MSN in vitro. Once transplanted into the lesioned striatum of rats these progenitors can survive and differentiate in MSN. On the other hand this xenografting experiments revealed that grafted cells have an extensive proliferation capacity. All the in vitro and in vivo data demonstrate that hES cells differentiation can be efficiently direct to a cell population relevant for cell therapy of HD. However these results underlines specific precautionary action on the path to the clinic, allowing for blocking cells proliferation if need be

Study of the therapeutic potential of human embryonic stem cells for cell therapy of HD

La maladie de Huntington (MH) est une maladie neurodégénérative rare, qui affecte les neurones GABAergiques moyens épineux (MSN) du striatum. Actuellement aucun traitement ne permet de guérir cette pathologie. Un essai clinique pilote, fondé sur la greffe intracérébrale de tissus fœtaux humains, a permis de remplacer les cellules lésées et de corriger certains symptômes. Néanmoins, la logistique nécessaire pour accéder à ces cellules limite cette forme de thérapie cellulaire à un nombre de patients restreint. Il est nécessaire d identifier une source alternative de cellules capables de remplacer efficacement les tissus fœtaux. Les cellules souches embryonnaires humaines (hES) possèdent deux propriétés essentielles, l autorenouvellement et la pluripotence, qui en font des candidats intéressants. L objectif de notre étude a été d évaluer le potentiel thérapeutique de ces cellules pour la thérapie cellulaire de la MH. Nous avons élaboré un protocole permettant la production, in vitro, de progéniteurs striataux capables de se différencier en MSN, à partir de cellules hES. Une fois greffés dans un striatum lésé de rat, ces progéniteurs peuvent survivre et se différencier en neurones MSN. Ces expériences de xénogreffes ont d autres parts révélés la présence de cellules neurales prolifératives persistantes. L ensemble de nos résultats démontre que les cellules hES constituent une source cellulaire alternative pertinente pour la thérapie cellulaire de la MH. Cependant, ils soulignent la nécessité de mettre en place des mesures spécifiques pour contrôler la prolifération in vivo des greffons issus de cellules hES, avant d envisager toute application clinique.Huntington s disease (HD) is a neurodegenerative monogenic disorder resulting primarily in loss of GABAergic medium spiny striatal neurons (MSN). There is no known treatment to cure this pathology. Recent clinical trials consisting in transplanting human fetal tissue into the striatum of HD patients resulted in the substitution of lost cells and lead to functional benefits. However, application of this treatment to a large number of patients is restricted because the source and the processing of fetal cells are limiting factors. Thus, it is necessary to identify an alternative source of cells suitable to replace efficiently fetal tissue. Human embryonic stem (hES) cells, because they are self-renewable and pluripotent, are prime candidates. The aim of our work was to evaluate the therapeutic potential of hES cells for cell therapy of HD. We have designed a protocol to direct the differentiation of hES cells toward a striatal neuronal fate. This protocol allows the production from hES cells of striatal progenitors that are able to differentiate in MSN in vitro. Once transplanted into the lesioned striatum of rats these progenitors can survive and differentiate in MSN. On the other hand this xenografting experiments revealed that grafted cells have an extensive proliferation capacity. All the in vitro and in vivo data demonstrate that hES cells differentiation can be efficiently direct to a cell population relevant for cell therapy of HD. However these results underlines specific precautionary action on the path to the clinic, allowing for blocking cells proliferation if need be.EVRY-Bib. électronique (912289901) / SudocSudocFranceF

Conductance-based phenomenological non-spiking model: a dimensionless and simple model that reliably predicts the effects of conductance variations on non-spiking neuronal dynamics

The modeling of single neurons has proved to be an indispensable tool in deciphering the mechanisms underlying neural dynamics and signal processing. In that sense, two types of single-neuron models are extensively used: the conductance-based models (CBMs) and the so-called 'phenomenological' models, which are often opposed in their objectives and their use. Indeed, the first type aims to describe the biophysical properties of the neuron cell membrane that underlie the evolution of its potential, while the second one describes the macroscopic behavior of the neuron without taking into account all its underlying physiological processes. Therefore, CBMs are often used to study 'low-level' functions of neural systems, while phenomenological models are limited to the description of 'high-level' functions. In this paper, we develop a numerical procedure to endow a dimensionless and simple phenomenological nonspiking model with the capability to describe the effect of conductance variations on non-spiking neuronal dynamics with high accuracy. The procedure allows to determine a relationship between the dimensionless parameters of the phenomenological 1 model and the maximal conductances of CBMs. In this way, the simple model combines the biological plausibility of CBMs with the high computational efficiency of phenomenological models, and thus may serve as a building block for studying both 'high-level' and 'low-level' functions of non-spiking neural networks

Conductance-based phenomenological non-spiking model: a dimensionless and simple model that reliably predicts the effects of conductance variations on non-spiking neuronal dynamics

The modeling of single neurons has proved to be an indispensable tool in deciphering the mechanisms underlying neural dynamics and signal processing. In that sense, two types of single-neuron models are extensively used: the conductance-based models (CBMs) and the so-called 'phenomenological' models, which are often opposed in their objectives and their use. Indeed, the first type aims to describe the biophysical properties of the neuron cell membrane that underlie the evolution of its potential, while the second one describes the macroscopic behavior of the neuron without taking into account all its underlying physiological processes. Therefore, CBMs are often used to study 'low-level' functions of neural systems, while phenomenological models are limited to the description of 'high-level' functions. In this paper, we develop a numerical procedure to endow a dimensionless and simple phenomenological nonspiking model with the capability to describe the effect of conductance variations on non-spiking neuronal dynamics with high accuracy. The procedure allows to determine a relationship between the dimensionless parameters of the phenomenological 1 model and the maximal conductances of CBMs. In this way, the simple model combines the biological plausibility of CBMs with the high computational efficiency of phenomenological models, and thus may serve as a building block for studying both 'high-level' and 'low-level' functions of non-spiking neural networks

A general pattern of non-spiking neuron dynamics under the effect of potassium and calcium channel modifications

International audienceElectrical activity of excitable cells results from ion exchanges through cell membranes, so that genetic or epigenetic changes in genes encoding ion channels are likely to affect neuronal electrical signaling throughout the brain. There is a large literature on the effect of variations in ion channels on the dynamics of spiking neurons that represent the main type of neurons found in the vertebrate nervous systems. Nevertheless, non-spiking neurons are also ubiquitous in many nervous tissues and play a critical role in the processing of some sensory systems. To our knowledge, however, how conductance variations affect the dynamics of non-spiking neurons has never been assessed. Based on experimental observations reported in the biological literature and on mathematical considerations, we first propose a phenotypic classification of non-spiking neurons. Then, we determine a general pattern of the phenotypic evolution of non-spiking neurons as a function of changes in calcium and potassium conductances. Furthermore, we study the homeostatic compensatory mechanisms of ion channels in a well-posed non-spiking retinal cone model. We show that there is a restricted range of ion conductance values for which the behavior and phenotype of the neuron are maintained. Finally, we discuss the implications of the phenotypic changes of individual cells at the level of neuronal network functioning of the C. elegans worm and the retina, which are two non-spiking nervous tissues composed of neurons with various phenotypes

A general pattern of non-spiking neuron dynamics under the effect of potassium and calcium channel modifications

Electrical activity of excitable cells results from ion exchanges through cell membranes, so that genetic or epigenetic changes in genes encoding ion channels are likely to affect neuronal electrical signaling throughout the brain. There is a large literature on the effect of variations in ion channels on the dynamics of spiking neurons that represent the main type of neurons found in the vertebrate nervous systems. Nevertheless, non-spiking neurons are also ubiquitous in many nervous tissues and play a critical role in the processing of some sensory systems. To our knowledge, however, how conductance variations affect the dynamics of non-spiking neurons has never been assessed. Based on experimental observations in the biological literature and on mathematical considerations, we first propose a phenotypic classification of non-spiking neurons. Then, we determine a general pattern of the phenotypic evolution of non-spiking neurons as a function of changes in calcium and potassium conductances. Furthermore, we study the homeostatic compensatory mechanisms of ion channels in a well-posed non-spiking retinal cone model. We show that there is a restricted range of ion conductance values for which the behavior and phenotype of the neuron are maintained