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La sclérose latérale amyotrophique (SLA) est une pathologie neurodégénérative, caractérisée par une dégénerescence progressive des motoneurones. Outre les motoneurones, d'autres types cellulaires du parenchyme nerveux seraient impliqués, notamment les astrocytes. De nombreux mécanismes cellulaires seraient à l'origine de cette dégénerescence, dont une excitotoxicité méd iée par Je glutamate. Ce travail se centre sur le récepteur mGluR5 du glutamate. Le mGluR5 est considéré comme Je senseur astrocytaire du glutamate et sa fonctionnalité est perturbée dans des cultures primaires d'astrocytes issus de rats transgéniques pour la hSODI 3 (modèle de SLA). L'activation du récepteur mGluR5 astrocytaire issus de rats WT entraîne une signalisation calcique cytosolique particulière de type oscillatoire. Or, nous observons dans des cultures primaires d'astrocytes issus de rats hSODI 3 une perte de ces oscillations calciques après stimulation du mGluR5.L'objectif de ce travail a tout d'abord été de comprendre les causes de cette altération de la signalisation calcique associée au mGluR5. Pour ce faire, nous avons étudié l'expression et la régulation par des médiateurs libérés dans la SLA du mGluR5 et des protéines intervenant dans sa signalisation calcique. Deux protéines ont retenu notre attention et pourraient potentiellement être à 1'origine des modifications de la signalisation calcique associée au mGluR5 : le mGiuR5 lui-même et la PKüDans un deuxième temps, nous avons étudié les conséquences que cette altération de la signalisation calcique associée au mGluR5 entraînerait. Ainsi, nous pensons qu'un profil calcique de type oscillatoire entraînerait une réponse cellulaire distincte qu'un profil calcique de type pic plateau. Nous avons formulé deux hypothèses quant aux rôles des oscillations calciques cytosoliques provoquées par la stimulation du mGluR5 :1)Le mGluR5 modulerait la fonction mitochondriale en induisant une signalisation calcique cytosolique qui influencerait elle-même la concentration calcique mitochondriale.2)Le mGluR5 modulerait l'activation de certains facteurs de transcription en induisant une signalisation calcique cytosolique.Parmi nos observations, nous avons constaté un défaut de capture mitochondriale de calciumaprès une stimulation du mGluRS dans des astrocytes prélevés sur des rats hSODl 093Par ailleurs, dans les manipulations réalisées, le mGluRS ne semblait pas intervenir dans l'activation du facteur de transcription étudié, NFAT.Ces résultats préliminaires soutiennent l'hypothèse d'une implication du mGluR5 dans la SLA. Les nombreuses années de recherche sur ce récepteur ont permis d'étudier son expression, sa structure et sa signalisation mais nous ignorons encore ses fonctions, méritant d'être élucidées dans le cadre de la SLA. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Other cell types of the central nervous system are also involved in the pathogenesis, including astrocytes. Several cellular mechanisms have been proposed to explain the Joss of motor neurons. Particularly, excitotoxicity induced by excessive stimulation of glutamate receptors seems to be a key aspect. This work is focused on the glutamate metabotropic receptor 5 (mGluR5). The mGluR5 is considered as the astrocytic glutamate sensor and its functions seems to be altered in primary cultures of cortical astrocytes from transgenic rats hSOD 1 3 (ALS mode!). The activation of astrocytic mGluR5 derived from WT (wild-type) rats leads to an oscillatory calcium response. In contrast, after mGluR5 activation in hSOD 1 3A rats astrocytes, we observe a Jack of calcium oscillations.The first aim of this work was to understand the causes regarding the alteration of the calcium profile after stimulation of the astrocytic mGluR5. Therefore, we studied the expression and regulation of mGluR5 and proteins involved in its calcium signaling in the presence of mediators released during ALS. We found that mGluR5 itself and PKCE could be involved in the alteration of the calcium signaling induced by the mGluR5 activation in hSODl 3 astrocytes.The second aim of this work was to understand the consequences that this altered calcium signaling might have. We strongly believe that oscillatory calcium profile and peak-plateau calcium profile induce distinct cellular responses. We formulated two different hypotheses about the putative fonctions of calcium oscillations. First, mGluR5 could influence mitochondrial fonction by inducing a cytosolic calcium profile that would itself influence the mitochondrial calcium concentration. The second hypothesis is that mGluR5 could modulate the activation of transcription factors by inducing a defined cytosolic calcium profile.Among our observations, we noted a defect in the mitochondrial calcium entry after mGluR5 stimulation in hSOD 1GA93 astrocytes. Besides that, after stimulation of astrocytic mGluR5, no differential regulation of transcription factor NFAT could be depicted in our experimental conditions (both in hSOOI 093A and WT astrocytes).These preliminary results reinforce the hypothesis that mGluR5 could be involved in the pathogenesis of ALS. Even though the structure, the signaling and the expression of mGJuR5 is being studied for several years, we still know only little about its real functions, and these deserve to be found particularly in the context of ALS.

Receptor, Metabotropic Glutamate 5 --- Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS), which was described since 1869 by Jean Martin Charcot, is a devastating neurodegenerative disease characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem and the spinal cord. The cognitive process is not affected and is not merely the result of aging because may occur at young ages. The only known cause of the disease is associated with genetic mutations, mainly in the gene encoding superoxide dismutase 1 (familial ALS), whereas there is no known cause of the sporadic form of ALS (SALS), which comprises >90% of cases. Both ALS types develop similar histopathological and clinical characteristics, and there is no treatment or prevention of the disease. Because effective treatments for ALS, as for other neurodegenerative diseases, can only result from the knowledge of their cellular and molecular pathophysiological mechanisms, research on such mechanisms is essential. Although progress in neurochemical, physiological and clinical investigations in the last decades has identified several mechanisms that seem to be involved in the cell death process, such as glutamate-mediated excitotoxicity, alterations of inhibitory circuits, inflammatory events, axonal transport deficits, oxidative stress, mitochondrial dysfunction and energy failure, the understanding of the origin and temporal progress of the disease is still incomplete and insufficient. Clearly, there is a need of further experimental models and approaches to discern the importance of such mechanisms and to discover the factors that determine the selective death of motor neurons characteristic of ALS, in contrast to other neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Whereas studies in vitro in cell cultures, tissue slices or organotypic preparations can give useful information regarding cellular and molecular mechanisms, the experiments in living animal models obviously reflect more closely the situation in the human disease, provided that the symptoms and their development during time mimics as close as possible those of the human disease. It is necessary to correlate the experimental findings in vitro with those in vivo, as well as those obtained in genetic models with those in non-genetic models, aiming at designing and testing therapeutic strategies based on the results obtained.

Neurology --- Medicine --- Health & Biological Sciences --- trophic factors --- motor neuron degeneration --- skeletal --- neuroinflammation --- muscle --- genetic expression --- spinal cord --- amyotrophic lateral sclerosis (ALS)