Thèses sur le sujet « Sclérose latérale amyotrophique – Génétique »
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Praline, Julien. « Génétique des formes sporadiques de sclérose latérale amyotrophique ». Thesis, Tours, 2009. http://www.theses.fr/2009TOUR3139/document.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The cause of sporadic cases (SALS) remains unknown but a genetic participation in a model of complex disease is suspected. Our work concerns two susceptibility genes for SALS: Apolipoprotein E gene (APOE) and the gene involved in familial hemochromatosis (HFE). Our first study including 1482 patients with SALS confirms a link between ε4 allele and bulbar-onset of the disease, only in men. We suggest a pathophysiological explanation with a role for the androgen receptor which is particularly abundant in motor neurons of the brainstem. Our second study about 244 patients and 302 controls did not find any association between the H63D polymorphism and SLAS, which has previously been showed. However, the Y allele of the C282Y polymorphism seems to exert a protective effect against SALS. We discuss these data within the pathophysiological hypothesis of oxidative stress in ALS
Renaud, Laurence, et Laurence Renaud. « L'impact de la mutation UBQLN2 sur la protéinopathie de TDP-43 dans la sclérose latérale amyotrophique et la démence fronto-temporale ». Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/37924.
Texte intégralLa sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative affectant les neurones moteurs supérieurs et inférieurs menant éventuellement à une paralysie générale du patient. Le décès du patient survient généralement entre 2 à 5 ans subséquemment à l’apparition des premiers symptômes. La SLA consiste en la maladie neurologique causant le plus décès chez l’adulte et il est estimé qu’environ 10% des cas sont familiaux (fSLA) et 90% sont sporadiques (sSLA). De plus, 15% des patients souffrant de la SLA développent également une démence fronto-temporale (DFT) s’illustrant par des troubles de comportements ainsi qu’un changement de personnalité majeur. Il a été démontré que la SLA et la DFT partagent un spectre génétique commun et les patients atteints de DFT démontrent une protéinopathie caractérisée par une accumulation anormale de certaines protéines dans le cytoplasme des neurones et des cellules gliales, tout comme pour les patients souffrant de SLA. Plusieurs gènes mutés ont été identifiés au cours des dernières années pour la forme fSLA, notamment superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), ubiquilin-2 (UBQLN2), Fused in sarcoma (FUS), optineurin (OPTN), etc. Un des gènes le plus étudié et le mieux décrit est celui codant la protéine TDP-43. Cette protéine nucléaire, lorsque mutée, est délocalisée dans le cytoplasme, où elle forme des inclusions anormales et persistantes. Ces agrégats, lorsque formés, renferment également plusieurs autres composés, notamment d’autres protéines telles qu’UBQLN2, différentes nucléoporines, ubiquitine, etc. UBQLN2 est une protéine ayant un rôle primordial dans le système de dégradation du protéasome (UPS) ainsi que pour l’autophagie. Cette protéine est responsable de la liaison entre les protéines destinées à être dégradées avec l’UPS. Il a été démontré dernièrement in vitro et in vivo que la mutation d’UBQLN2 est liée à l’agrégation de TDP-43. Cependant, le mécanisme exact de ce phénomène reste grandement incompris et nécessite encore beaucoup d’attention et de travail. Dans ce mémoire, nous avons utilisé pour notre étude des cellules en culture afin de surexprimer les formes natives et mutantes d’UBQLN2 humain (hUBQLN2) pour étudier l’effet d’UBQLN2 sur la protéine TDP-43. Notre équipe a réussi à démontrer dernièrement dans les cellules de neuroblastome de souris (Neuro2a) que la surexpression de l’UBQLN2 entraînait une délocalisation de TDP-43 du noyau vers le cytoplasme en plus de son accumulation anormale dans des agrégats. De plus, l’effet synergique entre les formes mutées de TDP-43 et UBQLN2 a également été démontré dans un modèle murin dans notre article paru en 2018 comme quoi la mutation d’UBQLN2 influence grandement la protéinopathie de TDP-43. À la suite de ces constats, nous avons orienté nos études sur le phénomène synergique entre UBQLN2 et TDP-43 qui est encore grandement méconnu. Pour ce faire, une analyse complète et exhaustive de la littérature a été effectuée afin de bien comprendre la mutation UBQLN2 et consiste en la première revue littéraire couvrant la totalité des ouvrages publiés sur la mutation d’UBQLN2 dans la SLA. Par la suite, nous avons convenu d’étudier l’effet de la mutation d’UBQLN2P497H sur le transport nucléo-cytoplasmique dans les cellules Neuro2a ainsi que dans les tissus de souris transgéniques. Les souris utilisées sont les mêmes que pour l’article Picher-Martel et al., 2018, soit des souris simple transgénique UBQLN2P497H et TDP-43G348C ainsi que la première souris double transgénique arborant UBQLN2P497H/TDP-43G348C. Les souris doubles transgéniques se sont avérées très intéressantes. En effet, elles ont développé les caractères typiques retrouvés chez les patients SLA/DFT avec une perte motoneuronale accompagnée de dégénérescence axonale, atrophie musculaire, gliose, trouble moteur ainsi que cognitif en plus d’agrégations cytoplasmique de TDP-43 importantes. À l’aide de ce modèle unique nous avons approfondi notre compréhension des déficits observés au niveau du transport nucléo-cytoplasmique, déficit grandement observé chez les patients SLA. Nous avons observé que le transport nucléo-cytoplasmique était davantage et significativement altéré dans les cellules co-transfectées avec les gènes encodant pour les deux protéines mutées plutôt que transfectées avec une seule. Nous avons également observé pour les souris double transgéniques comparées aux souris simples pour l’une ou l’autre de ces protéines. Nos résultats suggèrent donc que la mutation d’UBQLN2 exacerbe significativement la protéinopathie de TDP-43 et engendre une perturbation importante du transport nucléo-cytoplasmique ainsi que des complexes du pore nucléaire. En conclusion, ce mémoire démontre un rôle important de la mutation d’UBQLN2 sur TDP-43 et leur grande affinité à augmenter les déficits du transport nucléo-cytoplasmique. Ceci suggère donc qu’UBQLN2 et TDP-43 sont intimement liés et peuvent jouer un rôle synergique dans la physiopathologie de la SLA. Le modèle murin double transgénique pourra indubitablement être utilisé en laboratoire afin de tester de nouvelles approches thérapeutiques.
Moulard, Bruno. « Génétique de la sclérose latérale amyotrophique : études cliniques et moléculaires des formes familiales ; études moléculaires des formes sporadiques ». Montpellier 1, 1996. http://www.theses.fr/1996MON1T015.
Texte intégralCorcia, Philippe. « Facteurs de susceptibilité génétique dans la sclérose latérale amyotrophique : applications à l'étude des gènes SMN et SOD1 ». Montpellier 1, 2002. http://www.theses.fr/2002MON1T019.
Texte intégralHalter, Benoît. « Dérégulation du transcriptôme musculaire et analyse des mécanismes physio-pathologiques lors de la sclérose latérale amyotrophique ». Strasbourg, 2009. http://www.theses.fr/2009STRA6115.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease characterized by motorneuron death and muscular atrophy. Most cases are sporadic, however familial forms also exist, as a result of a dominant mutation in the superoxide dismutase 1 (SOD1) gene, which enabled the generation of animal models developing an experimental form of ALS. Several teams, including our lab, involve the muscle in the pathological process. We thus undertook a global study to investigate muscular transcriptome modifications during ALS pathology. This study generated a transcriptional "signature" of the disease, which could be used as basis to develop diagnostic tests, and revealed genes of interest in this pathology. First, we studied Rad because of its precocity and the intensity of its regulation in SOD1 mice, compared to wild type animals. We described the mechanisms regulating rad expression as well as the pathological phenomenon responsible for its induction. (Confirmed in human patients). Furhthermore, ALS is associated with hypermetabolism which, once compensated, increases animal’s survival. To better understand this hypermetabolism, we studied the implication of a second gene: the stearoyl-coenzyme-A desaturase 1 (SCD1) a key enzyme in mono unsatured fatty acids biosynthesis. SCD1 mRNA is specifically repressed in ALS muscle and its invalidation is known to trigger hypermetabolism in wild type animals. We thus hope to have identified one of the genes responsible for ALS-associated hypermetabolism. My work has therefore provided a muscular transcriptom "signature" in ALS and allowed us to identify target genes crucial for the fundamental understanding of the pathology
Hamidou, Bello. « Epidémiologie de la sclérose latérale amyotrophique : Facteurs de risque, incidence et phénotypes ». Thesis, Limoges, 2015. http://www.theses.fr/2015LIMO0062/document.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease. Currently in France, there is no population-based incidence data. The phenotypic profile of French patients with ALS, has not been studied. Lastly, no risk factors are confirmed for this pathology. In this context, to improve knowledge in these fields, our work consisted of three studies: (1) a study on the incidence of ALS in the Limousin region based on the database from the first French ALS register (2) a study of the phenotypes of patients from 11 French ALS centers and (3) a literature review of original epidemiological studies focusing on physical activity (PA) and ALS risk. Our work has highlighted a high crude and standardized incidence (on Europe population): 3.19 / 100 000 person-years (PY) and 2.58 / 100,000 PY respectively. Regarding phenotypic aspects, our work identified eight ALS phenotypes: (1) bulbar, (2) cervical spinal (3) lumbar spinal (4) flail leg, (5) flail arm, (6) respiratory, (7) ALS-FTD and (8) dropped head. We demonstrated that the PA itself is probably not a risk factor for ALS. As a first perspective we hope to expand the ALS Register to other French regions. In a second perspective, it would be very important to confirm our work on phenotypes on a larger and representative sample of ALS patients. Finally, regarding the relationship between PA and ALS, other work of high level of evidence are desirable to confirm the synthetic result we brought in this thesis work
Waegaert, Robin. « Etude du continuum mécanistique et physiopathologique entre la sclérose latérale amyotrophique et la démence frontotemporale ». Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ110.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) and FrontoTemporal Dementia (FTD) are two fatal and incurable neurodegenerative diseases. These two diseases share a clinical continuum supported by genetic and histological arguments. Today, about 15% of ALS patients develop later FTD symptoms and reversely. In 2006, mutations in the CHMP2B gene were discovered in ALS-FTD patients. Twelve years later, pathological mechanisms associated with mutations of this gene in the ALS-FTD syndrome are poorly understood. For a better understanding of CHMP2Bintron5-related pathological mechanisms, we studied by different approaches the impact of this mutation in a mouse model. Transcriptomic analysis on lumbar spinal cord highlighted a panel of deregulated cellular pathways, including the inflammatory response and the lipid metabolism. In addition, we showed an early disturbance of macroautophagy, with a blockage of final degradation step associated with a repression of autophagy initiation. Finally, our results show that neuron specific expression of CHMP2Bintron5 leads to muscular atrophy and structural and functional alterations of neuromuscular junctions
Maurel, Cindy. « Génétique de la Sclérose Latérale Amyotrophique et rôle de la voie de SUMOylation dans l'agrégation de la protéine TDP-43 ». Thesis, Tours, 2018. http://www.theses.fr/2018TOUR3315.
Texte intégralAmyotrophic Lateral Sclerosis (ALS), characterized by motor neuron degeneration, is influenced by genetic and environmental factors. The objective of this work was to improve knowledge on the genetic of ALS and to study the implication of a post-translationnal modification (PTM), SUMOylation, in the formation of cytoplasmic TDP-43 positive aggregates observed in a majority of ALS patients. We participated in an European genome-wide association study (GWAS) which described an association between new genetic loci, including the locus of the gene C21ORF2, and ALS risk. We also identified a novel mutation in a causal gene of ALS, TARBBP encoding TDP-43 protein. This mutation, p.N259S, present in an ALS patient with rapid progression, is the first described in the RRM2 domain of TDP-43. The surexpression of this mutant protein in vitro was associated with cytoplasmic aggregates positive for TDP-43 and ubiquitin. We suspected the SUMOylation pathway to be implicated in aggregates formation via a PTM of TDP-43. First, we observed that a global inhibition of protein SUMOylation by anacardic acid reduces TDP-43 positive aggregates, improves neuritogenesis and cell viability. We next showed, for the first time, that the mutation of the unique potential SUMOylation site of TDP-43, modifies the intracellular localization of TDP-43 positives aggregates, which become nuclear, and is associated in improvement in global cellular functions. Based on our results, we propose that the SUMOylation pathway is a mechanism regulating TDP-43 export from the nucleus to the cytoplasm. Blocking this export might represent a new therapeutic target by reducing the formation of TDP-43 positive aggregates in the cytoplasm of motor neurons
Vernay, Aurelia. « Caractérisation des souris CHMP2Bintron5, un modèle d'étude du continuum SLA-DFT ». Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ116/document.
Texte intégralThe neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) form a clinical, genetic and histopathological continuum. Mutations in CHMP2B can cause ALS or DFT. The aim of this study was to characterize a new transgenic mouse model based on the neuronal expression of the human mutation CHMP2Bintron5.The mice develop a progressive muscle weakness and motor coordination defects, associated with a distal alteration of the motoneurons. Moreover, their feeding behavior is altered and they develop social disinterest and stereotypies, while mnesic functions are spared. We observed protein aggregates in neurons and an astrocytosis, mirroring the histopathological profile of patients.The neuronal expression of the mutant CHMP2Bintron5 triggers a motor phenotype associated with dementia symptoms and histopathological hallmarks of ALS and FTD. This transgenic line willallow the study of the common mechanisms implicated in the ALS-FTD syndrom
Duque, Sandra. « Thérapie génique des maladies du motoneurone à l'aide de vecteurs dérivés des AAV ». Paris 7, 2009. http://www.theses.fr/2009PA077101.
Texte intégralMotor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS), are incurable degenerative disorders characterised by the selective loss of motor neurons (MNs) localised in the motor cortex, the brainstem and/or the spinal cord. To date, there is no treatment for these disorders because of the blood brain barrier (BBB) which hindered the crossing of the therapeutic molecules from the circulation flow to the central nervous System (CNS) parenchyma. New therapeutic strategies, based on gene transfer using viral vectors have thus been developed. This study aimed to evaluate new strategies for increasing the efficiency of MNs transduction using AAV vectors. The fîrst approach bypasses the problem of the BBB by injecting the viral vectors directly into brain areas at the origin of the descending spinal pathways. The injection of AAV vectors expressing therapeutic transgenes into these specific brain structures could indeed lead to the production and traffîcking of therapeutic proteins through descending pathways to the spinal cord by anterograde axonal transport mechanisms. The subsequent secretion of these proteins could thus influence the survival and the activity of the spinal cord MNs. The second approach is based on the systemic administration of a new serotype and genome AAV vectors, the self-complementary AAV9 vector. We identifîed the remarkable ability of AAV9 vectors to transduce cells of the CNS, including MNs, after a single intravenous injection in adult mice. This gene transfer strategy represents an efficient and non-invasive procedure to reach the CNS. This result raises thus great hopes for the treatment of MN disease and other neurological disorders
Le, Ber Isabelle. « Aspects cliniques et génétiques des dégénérescences lobaires frontotemporales ». Paris 5, 2008. http://www.theses.fr/2008PA05P631.
Texte intégralFrontotemporal lobar degenerations (FTLD) are rare neurodegenerative dementias characterized by behavioural and language disorders beginning in the sixth decade. In rare cases, FTLD is associated with motor symptoms of amyotrophic lateral sclerosis (ALS), in the same patient or within a family (FTD-ALS). The major pathological hallmarks of FTLD and FTD-ALS are neuronal cytoplasmic ubiquitin-positive inclusions (UBI+). Autosomal dominant transmission is observed in 20-50% of the patients with FTLD and FTD-ALS. However, the genes identified so far probably represent less than 20-30% of all FTLD families. No genes have been identified in FTD-ALS. Recently, three major advances were performed in this domain with the identification of PGRN mutations in FTLD, the discovery of TDP-4 as the major protein aggregated in UBI+ inclusions in FTLD and in FTD-ALS, and the identification of a novel locus on the 9p21-13 region in FTD-ALS families. We have studied the PGRN gene in pure FTLD and FTD-ALS and we have evaluated the frequency of mutations, enlarged the mutational spectrum and described the associated phenotypes. We have shown that TARDBP may be causally linked to the spectrum of FTLD disorders. We have studied the 9p region in FTD-ALS families and the main genes located in the interval by direct sequencing and by search of copy number variants (CNV) in 6 possibly 9p-linked families. The CNVs were also searched in a larger population of patients with FTLD and FTD-ALS. The identification of new genes implicated these disorders represent a major objective of research that will provide important insight into the pathophysiology of both FTLD and ALS disorders
Bourdeau-Julien, Isabelle. « ALS-associated RNA-binding protein FUS and mRNA translation regulation ». Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/68742.
Texte intégralMutations in several genes have been linked to amyotrophic lateral sclerosis (ALS),particularly in the gene coding for the Fused in Sarcoma protein (FUS). Those mutations are found in the part encoding for the nuclear localization signal, making the protein abnormallyabundant in the cytoplasm. Combined with other observations, it suggests that a toxic gainof function of FUS in the cytoplasm would be the cause of the neurodegeneration. ALS is a neurodegenerative disease that affects motor neurons and causes progressive paralysis. The molecular mechanisms causing the disease are still unknown. One of the hypotheses is the disruption of local translation of mRNAs, which allows synapses to respond quickly and independently from the cell body. Insufficient local translation to support long-term synapticactivity would lead to synaptic loss and neurodegeneration. Thereby, the objective of mystudy is to determine the role of FUS in the regulation of mRNA translation by characterizing its interaction with translational components and evaluate its function in an ALS-linked condition. I have shown that FUS is associated with stalled polyribosomes, which suggests that it plays a role in regulating mRNA translation by interacting with the core of translation.There is also an increase in the presence of FUS in the cytoplasm and in its interaction with polyribosomes following inhibition of translation through mTOR, suggesting its role as anegative regulator. In addition, ALS-related mutations amplify FUS inhibitory function bymaking FUS cytoplasmic and reducing protein synthesis. My results show that the FUSprotein would have a role as a translation inhibitor when it is cytoplasmic. There fore, increasing the presence of FUS in the cytoplasm in ALS would result in significant translation inhibition, at a level insufficient to support synaptic activity.
Von, Grabowiecki Yannick. « Les facteurs de transcription de la famille p53 dans l’atrophie musculaire : implications dans la Sclérose Latérale Amyotrophique et la cachéxie ». Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ126/document.
Texte intégralThe p53 family of transcription factors in muscular atrophy - Involvements in Amyotrophic Lateral Sclerosis and cachexia Muscular atrophy is a dangerous condition found in several diseases. In amyotrophic lateral sclerosis (ALS), a rare neuromuscular disease, as well as in cancer (phenomenon of cachexia), muscular atrophy can be fatal to patients.The transcription factors from the p53 family are involved in several cellular processes, facing cellular “stress” situations. Most notably, they can induce dell death or promote differentiation.We found, using cellular and mouse models of ALS and cachexia, that members of the p53 family are induced during muscular atrophy. This induction leads to the expression of canonnic target genes involved in cell death. Interestingly, TAp73, but especially TAp63, are able to activate the transcription of an effector or muscular atrophy called MuRF1. This proves that the p53 family cand participate in muscular atrophy by promoting the breakdown of muscle fibres.In addition, we used our mouse models to identifiy a new approach agains muscular atrophy.Indeed, we identified a derivative of tocopherol with interesting therapeutical proprieties
Palamiuc, Lavinia. « Etudes des altérations métaboliques musculaires au cours de la sclérose latérale amyotrophique : rôle dans le développement de la pathologie ». Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ088/document.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a fatal degenerative disease characterized by loss of upper and lower motor neurons, denervation and skeletal muscle atrophy. ALS is accompanied by metabolic alterations that are early events in mouse models for ALS. The main objective was to identify molecular targets responsible for these alterations. For this, we analyzed several metabolic regulators localized in presymptomatic glycolytic muscle tissue of an ALS mouse model, the SOD1G86R. We identified a pre-symptomatic alteration of metabolic equilibrium, showing an inhibition of glycolysis accompanied by an upregulation of lipid catabolic pathway. This alteration has functional significance, being reflected in a modified capacity of SOD1G86R mice to adapt to different types of exercise. Pharmacological inhibition of PDK4, one of the main inhibitors of glycolysis, delayed disease onset, underpinning the importance of metabolic equilibrium in disease progression. Taking into consideration the metabolic specificity of the different elements on the neuromuscular axis, this work opens towards new therapeutic approaches for ALS
Khalil, Bilal. « Importance du contrôle qualité des mitochondries dans les maladies neurodégénératives : analyse cellulaire et génétique dans des modèles drosophile de la maladie de Huntington et de la sclérose latérale amyotrophique ». Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5054.
Texte intégralMitochondria are the main energy source in neurons. Mitochondrial defects contribute to the development of neurodegenerative diseases, however they can be countered by a quality control system. The purpose of my thesis has been to determine if this system is dysregulated in Huntington’s disease (HD) and in amyotrophic lateral sclerosis (ALS) and if restoring it can be neuroprotective, by mainly using Drosophila models. HD, which is characterized by loss of striatal neurons, is caused by the mutant Huntingtin protein (mHtt). We showed that mHtt induces the accumulation of mitochondria in the retina. This could be due to a defect in mitophagy, a mechanism which allows the elimination of defective mitochondria and which is orchestrated by the protein PINK1. Interestingly, PINK1 overexpression ameliorates the abnormal phenotype of flies expressing mHtt. I also got interested in ALS, in which motor neurons degenerate, and mainly in the TDP-43 gene which is a major contributor to the disease. We showed that TDP-43 overexpression in Drosophila neurons leads to fragmentation of mitochondria due to decreased expression levels of the mitofusin gene. The latter controls the fusion process between healthy and damaged mitochondria and therefore the organelle integrity. We show that Mitofusin overexpression ameliorates locomotor defects and abnormal neuronal activity in flies expressing TDP-43. Our results show the importance of mitochondrial quality control in the pathogenesis of these diseases, and that reinforcing it can be beneficial
Calbiac, Hortense de. « Mechanisms of C9ORF72 pathogenicity and related autophagy impairment in amyotrophic lateral sclerosis Sqstm1 knockdown causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish ». Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS561.
Texte intégralTo investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS, we developed a zebrafish model of sqstm1 haploinsufficiency. We observed that loss of function of sqstm1 leads to a specific motor phenotype. To elucidate the common cellular mechanisms underlying motor neuron degeneration in ALS, we analyzedc9orf72 and sqstm1 epistatic interactions inzebrafish. C9orf72 and sqstm1 partial inhibitions have an additive effect and C9ORF72 rescues the phenotype induced by sqstm1 knockdown. Thus, both proteins belong to the same pathway and c9orf72 acts downstream of sqstm1. Also, we observed that depletion of these genes in mouse motor neurons primary cultures leads to the early death of motor neurons associated with autophagy impairment. To develop a vertebrate model that recapitulates the different mechanisms associated withthe C9ORF72 HRE pathogenicity in ALS, we combined the partial inhibition of c9orf72 with the expression of the DPRs in zebrafish. This induces a robust motor phenotype characterized by locomotor defects and paralysis. Focusing on GP repeats, we observed that the loss of function of c9orf72 is essential to inhibitpoly(GP) clearance.This is associated with SQSTM1/p62 accumulation, severe motor neurons abnormalities and loss. These phenotypes are rescued by the inhibition of caspase 9, a regulator of apoptosis. Also, rapamycinis able to improve the clearance of poly(GP) and p62, with restored swim and motor neurons features, thus confirming the role of C9ORF72 in autophagy.These results show that DPR toxicity is related to lowered expression of C9ORF72, suggesting that both gain and loss of function synergize in the C9ORF72 HRE pathogenicity
Lopez-Herdoiza, Maria Belen. « Modeling C9ORF72 loss-of-function : a knockdown mouse model ». Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066239/document.
Texte intégralThe GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The precise mechanisms through which the C9ORF72 mutation causes “c9FTD/ALS” have not yet been elucidated, but several hypotheses have been proposed. For my PhD project, in order I investigated the role of a partial loss of function of C9orf72 in ALS and FTD disease pathogenesis. For this, we have generated C9orf72 knock-down mice by targeting the RNA mouse orthologue of C9ORF72. We found that by knocking down C9orf72 intrinsically, mice develop social interaction deficits and depression like behavior, which relate to FTD-like anomalies. When looking for ALS-like abnormalities, we found that C9ORF72 knock-down mice have conserved spatial memory and normal motility through all their lifespan. However, they develop a lessening of strength that appears late and is maintained without aggravation. They do not present axonal loss or signs of muscle atrophy and/or wasting. Further analysis showed that C9orf72 knock-down mice present neuromuscular junction deficits at an old age that aggravate with further aging. These findings suggest that C9ORF72 partial loss of function leads disease pathogenicity course to a more likely FTD-like phenotype, and that gain of function toxicities caused by the expansion may be needed to trigger motor neuron disease and massive neurodegeneration
Schmitt, Florent. « Rôle de la stéaroyl-coenzyme A désaturase 1, une enzyme de synthèse des acides gras mono-insaturés, dans un modèle transgénique d’étude de la Sclérose Latérale Amyotrophique ». Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ085/document.
Texte intégralAmyotrophic lateral sclerosis is a neurodegenerative disease, associated with metabolic dysfunction. Alteration of lipid metabolism has been documented in ALS patients and animal models, and could participate to the first pathological steps of the disease. The objective of this thesis was to study the role of stearoyl-CoA desaturase 1 (SCD1), a key enzyme of lipid metabolism, in ALS. By studying the profile of peripheral fatty acids in an animal model of ALS, the SOD1 mice, we found that SCD1 activity was strongly reduced at early (sub-clinical) disease stage, and that this reduction could explain in itself the alteration of lipid metabolism characteristic of ALS. The impact of loss of SCD1 activity for the motor axis was then studied. Genetic deletion or pharmacological inhibition of SCD1 enhanced functional recovery after sciatic nerve injury in mice. Wefurther explored if the loss of SCD1 activity found in SOD1 mice is a protective mechanism elicited in response to ALS. We treated SOD1 mice with an inhibitor of SCD1 activity. The treatment resulted in exacerbated muscular oxidative metabolism,preservation of neuromuscular integrity and enhanced motor neuron survival. We conclude that inhibition of SCD1 represents a promising therapeutic target for ALS
Teyssou, Elisa. « Analyses génétiques et fonctionnelles de nouveaux gènes incriminés dans la Sclérose Latérale Amyotrophique (SLA) Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients ». Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066738.
Texte intégralThe fatal Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is characterized by the degeneration of upper and lower motor neurons. Most ALS cases are sporadic (SALS) whereas ~10% are familial (FALS). A growing number of genes has been identified in ALS and represent 70% of FALS and 10% of SALS. The aims of this project were to analyze the contribution of 6 rare genes in a large population of French ALS patients and to study the pathogenic impact of some identified variants.The first part of this work was dedicated to the genetic analysis of MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 and PFN1 genes. No causing variants were identified for MATR3 and CHCHD10 while 2 new variants, probably pathogenic, were identified for SS18L1, as well as 4 mutations for SQSTM1, 5 for UBQLN2 and 2 already reported mutations for PFN1. These analyses also highlighted a genetic overlap between ALS and other diseases: the Paget disease of bone for SQSTM1 and spastic paraplegia for UBQLN2. The second part of this work was to study the pathogenicity of some of the mutations identified in SQSTM1, UBQLN2 and PFN1 genes using analyses of (i) inclusions in ALS patient post-mortem tissue, (ii) protein expression and degradation pathways in patient lymphoblasts and/or (iii) cellular consequences after in vitro and in vivo overexpression. Our results showed prominent aggregation of mutant SQSTM1 (involved in autophagosomes formation), impaired lysosomal degradation and disrupted protein binding to HSP70 for mutant UBQLN2 and deregulated alternative autophagy and mitophagy pathways for mutant PFN1. Our results (i) precised the contribution of several genes in French ALS patients, (i) documented the genetic overlap between ALS and other diseases and (iii) highlighted the role of protein degradation pathways, especially autophagy, in the pathogenesis of ALS
Portet, Florence. « Troubles de la cognition dans la neurodégénérescence : intérêt prédictif des paramètres neuropsychologiques, fonctionnels, électrophysiologiques et génétiques : application à la SLA et à la maladie d'Alzheimer ». Montpellier 1, 2003. http://www.theses.fr/2003MON1T028.
Texte intégralDi, Scala Franck. « Analysis of skeletal muscle in amyotrophic lateral sclerosis : Etiological, diagnostic and therapeutic aspects ». Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR13188.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that attacks nerve cells in the brain and spinal cord, and produces muscle weakness and atrophy. ALS is emerging as a “multi-system” disease in which the alteration in muscle, motor neuron and glia cells may act synergistically to induce the disease. Although skeletal muscle is quite an untested tissue, many findings establish muscle as a promising primary target in ALS research. The aim of the present PhD work was to explore gene expression modifications in ALS skeletal muscle by conducting two independent approaches. First, our gene expression studies targeted Nogo-A and uncoupling protein 3 (UCP3). We showed that Nogo-A exhibits a specific pattern of expression in ALS skeletal muscle. This result, together with the observation that Nogo-A immunoreactivity correlates with the severity of motor impairment in ALS patients, suggest that Nogo-A expression in muscle could be used as a marker of ALS functional disability. As far as UCP3 is concerned, we showed that UCP3 is increased in ALS skeletal muscle, and stable in other ALS-like syndromes, suggesting that UCP3 is a potential marker for ALS diagnosis. Second, we extensively explored the transcriptome of human ALS muscle using a DNA microarray approach. This strategy enabled us to identify two groups of genes of particular interest from a clinical point of view. One group contain interesting candidates to measure disease progression and the other group contain interesting candidates for early diagnosis of ALS. In addition, several hits emerging from our data analysis are linked to retinoic acid (RA) metabolism and we currently explore the role of these alterations in ALS pathogenesis. Finally, we generated a molecular identity card of skeletal muscle affected by ALS, concretized by a database that might be a source to fill the gap in molecular targets for efficient therapeutic strategies
Bourefis, Annis-Rayan. « Novel FUS and CHCHD10 models to investigate pathogenic mechanisms in Amyotrophic Lateral Sclerosis ». Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS177.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder caused by progressive degeneration of upper and lower motor neurons (MNs), with a very rapid clinical course. It leads to muscle weakness and atrophy progressing to paralysis, with respiratory failure being the major cause of death within years following clinical diagnosis. Two major genes mutated in ALS patients are the RNA-binding protein FUS (FUSed in sarcoma), implicated in RNA metabolism, and coiled-coil-helix-coiled-coil-helix domain 10 (CHCHD10), which plays a role in mitochondria stability. Both these genes have been investigated through different model systems, from small invertebrate models to patient biopsies. However, the major phenotypic features obtained in these models are complex and often controversial. The objective of this work is to provide new insights on the implication of these genes in ALS through the use of new models.To investigate the pathogenic mechanisms induced by FUS and CHCHD10, we generated and characterized two novel stable non-sense mutant zebrafish models for the orthologues of these genes and highlighted several ALS phenotypic features. We demonstrated, for the FUS model but not for CHCHD10, reduced lifespan, locomotor disabilities, aberrant motor axons, disorganized neuromuscular junction (NMJ), muscle and mitochondrial alteration, as well as molecular changes. These findings indicate that loss of fus expression is responsible for the occurrence of distal pathological signs at the NMJ, thus supporting a “dying-back” neuronopathy, in which early disease hallmarks start at the level of the NMJ and progress towards MN cell bodies
Corbier, Camille. « Caractérisation d'un modèle murin knock out pour le gène C9orf72 ». Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ080.
Texte intégralAn expansion of G4C2 repeats in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). These repeats lead to DNA epigenetic changes resulting in a decrease expression of C9ORF72. To better understand the functions of this protein, we generated a C9orf72 KO mouse model. These mice do not develop an ALSphenotype, but present immune dysfunctions characterized by a splenomegaly and a lymphadenopathy. Sera and immunohistochemistry analysis also revealed elevated autoantibodies and a glomerulonephropathy, leading to mice death. To further investigate this phenotype, we generated different mice models with a tissue specific KO of C9orf72 in the main immune cell populations. Interestingly, the loss of C9orf72 in dendritic cells reproduce the splenomegaly and lymphadenopathy. Immunophenotyping of the dendritic cell lineage of KO mice revealed specific alteration of the plasmacytoid dendritic cells(pDCs). Overall, these results suggest that pDC could be the starting point of the inflammatory dysfunctions observed in C9orf72 KO mice
Pietri, David. « Structure and function of the C9ORF72-SMCR8-WDR41 complex and its implication for Amyotrophic Lateral Sclerosis (ALS) ». Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ087.
Texte intégralAmyotrophic lateral sclerosis (ALS or Charcot disease) is the third most common neurodegenerative disease. The main genetic cause of ALS is an expansion of GGGGCC repeats in the C9ORF72 gene which protein forms a complex with the SMCR8 and WDR41 proteins. To better understand its molecular functions, solving its structure was a main goal of my thesis. In parallel, we discovered that C9ORF72 regulates a newly described mechanism of biogenesis of newly-formed lysosomes, called autophagic lysosome reformation (ALR). This process has been extensively investigated during my thesis, in order to better understand its regulation, particularly for the regeneration of lysosomes in basal conditions and amino acid deprivation. My work reveals a new partner of the C9ORF72 complex as a novel function in lysosome biogenesis. These results could thus explain the dysfunction of lysosomes and neurodegeneration observed in ALS, which open new therapeutic ways for this devastating disease
Coque, Emmanuelle. « La neuroimmunité dans la sclérose latérale amyotrophique ». Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT095.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the selective loss of upper and lower motoneurons. Symptoms appears as muscular weakness, which irrevocably leads to muscle paralysis and death of patients within 3 to 5 years after onset of symptoms. An inflammatory response, along with the accumulation of blood-derived immune cells in the central nervous system (CNS) is a hallmark of the disease. This work proposes to investigate the role of resident cells of the brain, such as astrocytes and especially peripheral immune cells such as T CD8+ lymphocytes, in ALS pathogenesis. We show that once infiltrated in the CNS of SOD1G93A mice, CD8+ T cells become activated and undergo an oligoclonal expansion. In vitro, CD8+ T cells isolated from ALS mouse model (SOD1G93A strain) can trigger motoneuron death, in a manner that is dependent on the recognition of the MHC class I by TCR. We report that peripheral immunodepletion of CD8+ T cells is not sufficient to improve lifespan of SOD1G93A mice, but still permit to protect motoneurons from neurodegeneration. A genetic approach will confirm implication of CD8+ T lymphocytes in the disease
Vercruysse, Pauline. « Altérations hypothalamiques dans la sclérose latérale amyotrophique ». Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ064/document.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) is a major neurodegenerative disease characterised by a loss of upper and lower motor neurons. The loss of motor neurons leads to muscle atrophy and paralysis. Besides motor loss, weight loss is important in ALS patients. This symptom appears before first muscular symptoms and is correlated with survival. This defect of energetic metabolism is partially due to hypermetabolism associated with food intake problems. Hypothalamus is the part of brain controlling the energetic metabolism. The aim of my Ph.D. was to characterise hypothalamic alterations in ALS. First, we have shown a default in the melanocortin system of hypothalamus, and shown that this melanocortin defect correlates with alterations in food intake behaviour. Second, we demonstrated the existence of hypothalamic atrophy in ALS patients in the posterior part of the hypothalamus, including the lateral hypothalamic area (LHA). This atrophy was correlated with weight loss. Finally, we observed that hypothalamic MCH neurons, located in the LHA, are affected in ALS, and that MCH complementation rescues weight loss in a mouse model of ALS
Moumen, Radouane. « Sclérose latérale amyotrophique sporadique et stress oxydatif ». Caen, 2001. http://www.theses.fr/2001CAEN2067.
Texte intégralFergani, Anissa. « Altérations métaboliques dans la sclérose latérale amyotrophique ». Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13132.
Texte intégralAraujo, de Abreu Paula. « Role of p53 in muscle wasting ». Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ065/document.
Texte intégralMuscle atrophy in cachexia results from the imbalance between protein synthesis and degradation due to activation of the ubiquitin-proteasome pathway. Literature suggests that p53 family members play a role in controlling proliferation, differentiation and death of precursors and muscle fibers. Here we characterize the expression profile of the p53 family members in muscle atrophy in ALS (Amyotrophic Lateral Sclerosis) and in doxorubicin induced cachexia model. We revealed an increased expression of the p53 family members and atrogenes in a correlated manner on both models and a transcriptional activation of Trim63 by p53, p63 and p73. Importantly, we also show that ROS and ceramide accumulation are important for Trim63 induction by doxorubicin. In addition, we tested whether compounds of tocopherol harboring antioxidant activity might reduce muscle atrophy. We showed that this compound counteracts the induction of the Notch pathway, important to muscle development and regeneration
Abou, Ezzi Samer. « Chromogranines et pathogenèse de la sclérose latérale amyotrophique ». Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27148/27148.pdf.
Texte intégralMarin, Benoît. « Epidémiologie de la Sclérose Latérale Amyotrophique : incidence, mortalité et facteurs pronostiques nutritionnels de survie ». Limoges, 2011. https://aurore.unilim.fr/theses/nxfile/default/6e7490ac-2f22-4fb7-a39e-68b5b383ccbb/blobholder:0/2011LIMO310C.pdf.
Texte intégralTo date, few data have been published on the incidence of Amyotrophic lateral sclerosis in France. Clinically, progression of ALS is marked by a progressive deterioration in nutritional status. However, the value of new nutritional markers (such as the phase angle) should be considered, and our understanding of changes in nutritional status during the course of the disease remains fragmentary- During our PhD Thesis we performed an epidemiological descriptive study, a geoepiemiological study, two reviews and two prognostic studies. When age-standardized for the 1999 French population, the mean annual incidence was 2. 0/100,000 inhabitants (95% confidence interval (CI): 1. 8-2. 3). We also identified three clusters of ALS in Limousin. Phase angle is altered in ALS patients as compared to healthy controls and is independently associated with survival. We also demonstrated a significant weight loss at diagnosis, a progressive worsening of this parameter during the course and a significant and independent prognostic value of weight loss measured at diagnosis with a 30% increased risk of death for a 5% decrease from usual weight. One of our perspectives is to establish a registry of ALS in Limousin. A second perspective involves, using the ALS clusters we identified, to examine the possible link between ALS and L-BMAA cyanotoxin. Finally, concerning nutritional aspects of ALS our results support (i) early consideration of making assessment of the patient's weight and weight loss part of daily routine, and (ii) the establishment of experimental studies aiming to reverse weight loss and alter body composition of patients as quickly as possible after diagnosis
Camu, William. « Sclérose latérale amyotrophique : étude critique des principaux facteurs étiopathogéniques, perspectives ». Montpellier 1, 1989. http://www.theses.fr/1989MON11149.
Texte intégralGil, Yacobazzo Juan. « Epidémiologie comparée de la Sclérose Latérale Amyotrophique en Limousin, Franc - Uruguay ». Limoges, 2008. http://aurore.unilim.fr/theses/nxfile/default/7286bc00-2b75-40b0-a28a-8af212974fbd/blobholder:0/2008LIMO310I.pdf.
Texte intégralGordon, Paul H. « Sclérose latérale amyotrophique : mortalité, facteurs prédictifs de la survie ». Phd thesis, Université Pierre et Marie Curie - Paris VI, 2012. http://tel.archives-ouvertes.fr/tel-00829569.
Texte intégralEl, Oussini-Ben Chaabane Hajer. « Rôle des neurones sérotoninergiques dans la sclérose latérale amyotrophique ». Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ030/document.
Texte intégralAmyotrophic lateral sclerosis (SLA) is a neurodegenerative disease characterize by the loss of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. The loss of motor neurons leads to muscle atrophy and progressive paralysis. In 2013 our laboratory identified a new neuronal population affected in ALS. They observed the degeneration of serotoninergic neurons in ALS patients and animal models. For this, the aim of my PhD is to identify the role of serotoninergic neurons in case of ALS. We observed an upregulation of serotonin receptor 5-HT2B in ALS mice models. The investigation of the role of 5-HT2B receptor in case of ALS showed its role as a disease modulator. The loss of 5-HT2B receptor accelerated disease progression and modulated neuroinflammatory response. Moreover, our results showed that the loss of serotoninergic neurons is responsible of the development of spasticity, a painful symptom observed in ALS patients. All these opened the way for therapeutic strategies targeting spasticity and neuroinflammation in case of ALS
Chiot, Aude. « Implication des macrophages périphériques dans la Sclérose latérale Amyotrophique ». Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS595.
Texte intégralMicroglial cells and peripheral macrophages participate to motor neuron degeneration in ALS. However, the precise role of the peripheral macrophages surrounding motor neuron axons had not been discriminated from the role of CNS microglia. Although microglia and peripheral macrophages share common characteristics both populations have different developmental origins and are located in different cellular environments, which could lead to specific implications in the disease. In this study, we aimed to characterize the implication and the site of action of peripheral macrophages in ALS. We first confirmed the activation of peripheral macrophages in the sciatic nerve of two different mouse lines (expressing mutant SOD1) with different disease progression. We also showed for the first time the presence of macrophages surrounding motor neuron axons in the ventral root of a human ALS case. We showed that infiltration of macrophages in the spinal cord was minimal during the disease and was dependent on disease progression. Our transcriptional analyses showed major differences between microglia and peripheral macrophages even though both populations displayed a complex inflammatory profile. Finally, replacement of mutated macrophages by cells more neurotrophic or less neurotoxic led to an improvement of several pathophysiological markers and delayed symptomatic stage of the disease in ALS mice. In conclusion, we provide new evidence suggesting an active role of peripheral macrophages in ALS, supporting future therapeutic strategies by targeting peripheral macrophages
Sangari, Sina. « Atteintes sensorimotrices dans la sclérose latérale amyotrophique chez l'homme ». Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066302/document.
Texte intégralAmyotrophic Lateral Sclerosis is an adulthood neurodegenerative disease characterized by loss of motor neurons. Considered as a purely motor pathways disease, some investigations brought evidences for early and parallel sensory pathway impairments and for interneuron impairments that could precede and lead to motor neuron hyperexcitation. Although motoneuron activity is closely associated to sensory afferents and interneurons, their effects onto motoneuron excitation and their involvement in impairment spreading have not been studied yet. The aim of this thesis was on one hand, to confirm and characterize anatomically and functionally sensory impairment at spinal and cortical level in patients at the early stage of the disease and, on the other hand, to assess effects induced by these inputs onto motoneuron activity and through cervical and lumbar interneurons. Research project originality was to focus on proximal muscles clinically unaffected of which « presymptomatic » motoneurons receive sensory inputs from distal muscles clinically affected. We showed that: 1) despite their reduction, sensory inputs induce an hyperexcitation of motoneurons; 2) excitability and state of these motoneuron pools are normal through corticospinal afferents but are hyperexcited by peripheral afferents; 3) activity of cervical and lumbar propriospinal system and recurrent inhibition are reinforced
Cordier, Jérôme. « L'Assistance nutritionnelle dans la sclérose latérale amyotrophique : l'expérience montpelliéraine ». Montpellier 1, 2000. http://www.theses.fr/2000MON11019.
Texte intégralChatoui, Abdelfettah. « Ventilation à domicile des malades atteints de sclérose latérale amyotrophique ». Montpellier 1, 2000. http://www.theses.fr/2000MON11068.
Texte intégralDupuis, Luc. « Sclérose Latérale Amyotrophique : Mécanismes physiopathologiques et découverte de marqueurs biologiques ». Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13025.
Texte intégralLangou, Karine. « Développement de nouveaux modèles expérimentaux de la Sclérose Latérale Amyotrophique ». Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22033.
Texte intégralALS is a neurodegenerative disease characterized by a selective loss of motor neurons. A mutation in VAPB protein has been associated with ALS. VAPB, an endoplamic reticulum (ER) resident protein is proposed to play a role in protein transport and in the unfolded protein response. To manipulate VAPB (hVAPBwt and hVAPBp56s) expression in motor neurons in vitro, I used the viral gene transfer technology. hVAPBp56s induces selective motor neuron death which involved an ER-related pathway dependent on calcium signals. Studies on Cos-7 cells showed that hVAPBwt and hVAPBp56s impair the proteasome activity through the activation of ER stress and the sequestration of the 20S subnit. Moreover, we developed transgenic mice overxpressing hVAPBp56s which do not display any motor disorder
Bruneteau, Gaëlle. « Etude de la jonction neuromusculaire dans la sclérose latérale amyotrophique ». Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066097/document.
Texte intégralAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, usually leading to death in 3 to 5 years. The only treatment currently available, riluzole, has a modest effect on survival. Functional alterations of the neuromuscular junction (NMJ) have been reported in ALS, but their pathophysiological significance remains unknown. We studied the morphology of neuromuscular junctions in muscle samples collected from 11 ALS patients, using confocal and electron microscopy. Functional analysis of the NMJs was performed using surface-recording of compound motor action potentials after repetitive nerve stimulation at slow stimulus rate. A significant decrement (>10%), suggesting impairment of the neuromuscular transmission, was present in 45% of the patients. Morphological alterations of the NMJs were present in all ALS patients even at the early-stages. Beside denervation-induced morphological changes, one third of the NMJs showed abnormal spike-like areas of the outer edge of the postsynaptic primary gutter. A marked interposition of the terminal Schwann cell between the nerve terminal and the postsynaptic membrane, which was likely to alter synaptic transmission, was sometimes present. We found a significantly greater compensatory reinnervation in muscle from patients with slowly progressive ALS. Furthermore, we identified that the muscle molecular factor histone deacetylase 4 could play a key role in muscle reinnervation and disease progression in patients with ALS. This work has highlighted the presence of major morphological changes at the NMJs of ALS patients and identified potential new targets for future treatment
Echaniz-Laguna, Andoni. « Etude de la fonction mitochondriale et de l'expression du gène Nogo dans le muscle squelettique dans la sclérose latérale amyotrophique sporadique chez l'homme ». Université Louis Pasteur (Strasbourg) (1971-2008), 2006. https://publication-theses.unistra.fr/public/theses_doctorat/2006/ECHANIZ-LAGUNA_Andoni_2006.pdf.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a lethal disease characterized by degeneration of motoneurons. ALS is usually a sporadic condition of unknown origin. No specific diagnostic marker of ALS exists. It was recently proposed that mitochondrial abnormalities may be involved in ALS pathophysiology. In this work, we performed a temporal study of mitochondrial function in skeletal muscle in patients with ALS using the skinned fiber technique. We demonstrated that mitochondrial function was progressively altered in skeletal muscle in ALS as the disease develops. However, this alteration may not be specific of ALS and may simply be the result of denervation. Nogo is a reticulon-type protein and a member of the myelin-associated proteins superfamily. The Nogo gene encodes several isoforms of the protein, including Nogo-A. Recent observations suggest that Nogo-A expression in skeletal muscle may be used as a diagnostic marker of ALS. In this work, we performed a study of Nogo-A expression in skeletal muscle of patients with lower motor neuron disease. Our results suggest that Nogo-A expression in skeletal muscle of these patients may predict which ones will eventually develop ALS. We also contributed to a study demonstrating that the expression of Nogo-A in skeletal muscle in ALS was correlated with the severity of the disease and with muscle fiber atrophy
Le, Stunff Isabelle. « La sclérose latérale amyotrophique (SLA) : Commentaires sur le traitement symptomatique conduit à l'Hôtel Dieu ». Paris 5, 1992. http://www.theses.fr/1992PA05P062.
Texte intégralAebischer, Julianne. « Mécanismes de neurodégénérescence associés au processus inflammatoire dans la sclérose latérale amyotrophique ». Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX22067.
Texte intégralAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting primarily motoneurons in the brain and spinal cord. Symptoms of the disease include general muscle weakness, rapidly evolving in an overall paralysis, leading to the death of the patient. The precise mechanisms responsible for the selective vulnerability of motoneurons remain largely unknown, impeding therefore the development of effective therapies. My thesis work led to the discovery of a novel motoneuron selective death pathway dependent on the activation of LT-βR by LIGHT. This death pathway might also be triggered by the pro-inflammatory cytokine interferon gamma (IFNγ). Interestingly, we have documented signs of activation of this pathway in ALS mice and sporadic ALS patients, with IFNγ being upregulated in astrocytes and motoneurons. Furthermore, a genetic approach has provided evidence of the functional involvement of this death pathway in the pathogenic process
Coulombe, Zoé. « Surexpression de facteurs neurotrophiques dans un modèle murin de sclérose latérale amyotrophique ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/MQ55746.pdf.
Texte intégralGowing, Geneviève. « Le rôle de l'inflammation et des microglies dans la sclérose latérale amyotrophique ». Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26199/26199.pdf.
Texte intégralMoulard, Bruno. « La sclérose latérale amyotrophique familiale : étude de 13 familles montpelliéraines. Revue de la littérature : comparaison des phénotypes des formes familiales aux formes sporadiques : comparaison des différents phénotypes familiaux ». Montpellier 1, 1994. http://www.theses.fr/1994MON11118.
Texte intégralGuillem, Jean-François. « Histoire naturelle de la sclérose latérale amyotrophique : étude de l'évolution clinique de la maladie ». Montpellier 1, 1998. http://www.theses.fr/1998MON11078.
Texte intégralBayle, Lydie. « Amylose AL et maladie de la corne antérieure : une association peut-être non fortuite ». Rouen, 1991. http://www.theses.fr/1991ROUEM023.
Texte intégral