Дисертації з теми "Sclérose latérale amyotrophique – Modèles mathématiques"
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Ortholand, Juliette. "Joint modelling of events and repeated observations : an application to the progression of Amyotrophic Lateral Sclerosis." Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS227.
Повний текст джерелаProgression heterogeneity in chronic diseases such as Amyotrophic Lateral Sclerosis (ALS) is a significant obstacle to developing effective treatments. Leveraging the growing wealth of large databases through modelling can help better understanding it. However, the data collected only offer access to partial trajectories, that need to be realigned to reconstruct a comprehensive disease progression. To address this challenge, data-driven progression models like the longitudinal Spatiotemporal model were developed. Its main interest is its ability to synchronise patients onto a common disease timeline (temporal aspect) thanks to a latent disease age, while also capturing the remaining variability through parameters that account for outcome ordering (spatial aspect). However, this model was primarily designed for longitudinal data, overlooking crucial outcomes in ALS such as time to death or initiation of life support, like Non-Invasive Ventilation (NIV). Conversely, existing joint models offer the advantage of simultaneously handling longitudinal and survival data. However, they do not realign trajectories, which compromises their temporal resolution. This thesis aimed to expand the Spatiotemporal model into a Joint Spatiotemporal model, enabling, for ALS research, the examination of survival data alongside longitudinal data. First, we applied the Spatiotemporal model to explore how the interaction between sex and onset site (spinal or bulbar) impacts the progression of ALS patients. We selected 1,438 patients from the PRO-ACT database. We demonstrated a significant influence of both sex and onset site on six longitudinal outcomes monitoring the functional and respiratory decline in addition to Body Mass Index. However, this study did not incorporate survival analysis, despite its paramount importance in ALS, due to limitations inherent to the Spatiotemporal model. To address this gap, we associated the Spatiotemporal model with a survival model that estimates a Weibull survival model from its latent disease age, creating a univariate Joint Temporal model. After model validation, we benchmarked our model with a state-of-the-art joint model on PRO-ACT data. Our model exhibited significantly superior performance in terms of absolute bias and mean cumulative AUC for right-censored events. This demonstrated the efficacy of our approach in the context of ALS compared to existing joint models. However, modelling several longitudinal outcomes requires a multivariate approach. Life support initiation that might be censored by death needs to be also considered. We thus extended the Joint Temporal model, into a multivariate Joint Spatiotemporal model with competing risks to analyse NIV initiation. This involved coupling the multivariate Spatiotemporal model with a cause-specific Weibull survival model from the latent disease age. We incorporated spatial parameters with a Cox proportional effect on the hazard. After validation, we benchmarked our model with a state-of-the-art joint model on PRO-ACT data and analysed sex and onset site interaction in complement to the first study. The Joint Spatiotemporal model achieved similar performance to the state-of-the-art model while capturing an underlying shared latent process, the latent disease age, whereas the state-of-the-art models the impact of longitudinal outcomes on survival. To enhance the reproducibility and facilitate the reuse of these models, the proposed models were implemented in the open-source software Leaspy. In conclusion, this thesis introduces the first data-driven progression model combining longitudinal and survival modelling. We demonstrated its relevance to understand the occurrence of critical events in ALS. This work paves the way for further extension to analyse recurrent events, among other potential applications in causal inference
Langou, Karine. "Développement de nouveaux modèles expérimentaux de la Sclérose Latérale Amyotrophique." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22033.
Повний текст джерелаALS 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
Abou, Ezzi Samer. "Chromogranines et pathogenèse de la sclérose latérale amyotrophique." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27148/27148.pdf.
Повний текст джерелаPicchiarelli, Gina. "Rôle du muscle squelettique dans la Sclérose Latérale Amyotrophique : apport de modèles transgéniques conditionnels." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ054.
Повний текст джерелаAmyotrophic lateral sclerosis is a neurodegenerative whose first symptoms generally appear around age 60. It is characterized by progressive motor neuron degeneration, paralysis and leading to death due to respiratory failure in a few years. Currently, there is no cure so the understanding of ALS physiopathology is necessary. Although many alterations in the muscle have been highlighted, its contribution in ALS remains to be defined. We showed that FUS is enriched in subsynaptic nuclei and this enrichment depended on innervation. Besides, FUS binds directly acetylcholine receptors (AchR) promoter and is required for Ermdependent induction of AChR expression. Conversely, mutant FUS is enriched on extra-synaptic nuclei and induce muscle intrinsic toxicity responsible for neuromuscular junction (NMJ) alteration. Beyond NMJ, FUS is required for muscle mitochondrial function and muscle differentiation through PRMT1-dependent MEF2A activation. Thus, FUS muscular toxicity plays a key role in the ALS physiopathology
Mesci, Pinar. "L’implication du système xc- et du glutamate microglial dans les modèles murins de la sclérose latérale amyotrophique (SLA)." Paris 6, 2013. http://www.theses.fr/2013PA066286.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease leading to paralysis and death of patients. Mutations in SOD1 are responsible for motor neuron degeneration through a non-cell autonomous mechanism. Microglial cells, the macrophages of the central nervous system, participate in the progression of the disease. Since ALS is mainly sporadic, targeting the symptomatic phase during which microglial cells are actively involved is relevant to ALS. Since microglial neurotoxic factors are still largely unidentified in ALS and excitotoxicity is one pathway suggested to cause motor neuron death, our hypothesis was to assess if glutamate released by microglia through system xc- (a cystine/glutamate antiporter with the specific subunit xCT) could participate to motor neuron death in ALS. We now show that primary microglial cells expressed xCT and to a higher level upon activation, that xCT transcripts were enriched in microglia compared to the whole spinal cord and absent in motor neurons. In addition, xCT mRNA levels were increased in mutant SOD1 mouse spinal cords during disease progression. Deleting xCT in mutant SOD1 mice accelerated the onset of the disease but increased the duration of the symptomatic phase. Microglial system xc- was responsible for release of glutamate by microglial cells and deleting xCT increased the neurotrophic profile of microglial cells. These results show that system xc- could be a good target to slow ALS disease progression
Gowing, 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.
Повний текст джерелаHalter, Benoît. "Dérégulation du transcriptôme musculaire et analyse des mécanismes physio-pathologiques lors de la sclérose latérale amyotrophique." Strasbourg, 2009. http://www.theses.fr/2009STRA6115.
Повний текст джерелаAmyotrophic 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
Patel, Priyanka. "Development of new therapeutic approaches in mouse models of Amyotrophic Lateral Sclerosis." Doctoral thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/25851.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. Although numerous pathological mechanisms have been elucidated, ALS still remains a medical mystery in the absence of any effective therapy. Riluzole is the only therapeutic drug approved for ALS with regard to prolonging survival. Here, we have developed two strategies for treatment of ALS, first targeting the misfolded SOD1 (chapter 2) and other targeting neuroinflammation (chapter 3). In chapter 2, we aimed to reduce the level of misfolded SOD1 species in the nervous system. We tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the adeno-associated virus encoding the single chain antibody in SOD1G93A mice delayed disease onset and extended the life span by up to 28%, in direct correlation with scFv titers in the spinal cord. Our second treatment strategy which is aimed to target neuroinflammation is based on previous reports from our lab where it has been shown that Withaferin A (WA), an inhibitor of NF-κB activity was efficient in reducing disease phenotype in TDP-43 transgenic mouse model of ALS. We tested WA in mice from two transgenic lines expressing different ALS-linked SOD1 mutations, SOD1G93A and SOD1G37R. The beneficial effects of WA in SOD1G93A mice model was accompanied by alleviation of neuroinflammation, decrease in level of misfolded SOD1 species in spinal cord, a reduction in loss of motor neurons, resulting in delayed disease progression and mortality. Based on these evidences, AAV encoding a secretable scFv against misfolded SOD1 and WA should be considered as a potential treatment for ALS.
Pambo-Pambo, Arnaud Brice. "Etude du développement postnatal des motoneurones lombaires de deux souches de souris transgéniques, modèles de la sclérose latérale amyotrophique." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20716.
Повний текст джерелаThe SOD1 murine models of Amyotrophic Lateral Sclerosis (ALS) allowed major progress in the understanding of mechanisms which could lead to a selective loss of motoneurons (Mns), but these models display differences in the severity and time course of the disease. Changes in intrinsic properties of motoneurons may induce changes in excitability and intracellular calcium homeostasis leading to motoneuron death.Therefore, we studied electrophysiological properties of lumbar Mns from SOD1G85R and SOD1G93A mice, low expressor lines, during the first two postnatal weeks in order to identify possible early presymptomatic abnormalities. Our studies were carried out on two in vitro preparations: the whole isolated spinal cord and acute spinal cord slices. Mutant Mns display, in the two preparations, a modified action potential characterized by an increased duration due to a decrease of the maximal speeds of depolarisation and repolarisation and a reduction of the spike amplitude. These alterations appeared between P2-P5 in SOD1G85R Mns and between P6-P10 in SOD1G93A Mns and suggest a decrease of the density of sodium and potassium channels related to action potential. We also showed on spinal cord slices between P6-P10 that the gain of frequency decreases for SOD1G85R Mns and increases for SOD1G93A Mns without any change in the density of persistent inward sodium or calcium currents in these different mutant Mns. We observed also that the resting membrane potential of SOD1G93A Mns on spinal cord slices is decreased. The membrane properties of SOD1G85R Mns between P6-P10 were less susceptible to changes in presence of an extracellular calcium overload. Differential effects of this extracellular calcium overload on membrane properties of WT and SOD1G85R Mns could be due to different alterations of the potential dependence of voltage-gated channels and/or to the modulation of some types of channels sensitive to extracellular calcium. An over-branching of dendritic arborization, similar to that previously described in SOD1G85R Mns, was observed in SOD1G93A at P8-P9 with the above-mentioned action potential alterations and a weak rheobasic current. These morphogical and electrical changes could indicate together alterations of kinetics and/or density of channels on different sites on these Mns. In conclusion, our work shows on one hand that SOD1G85R and SOD1G93A mutations induce similar alterations of lumbar Mns properties but time-shifted in these two murine models and on the other hand that some alterations seem to be specific to a given SOD1 mutation
Leparc-Goffart, Isabelle. "Modèles de persistance des entérovirus : myocardiopathie expérimentale murine à coxsackievirus B3 et syndrome post-poliomyélitique chez l'homme." Lyon 1, 1995. http://www.theses.fr/1995LYO1T294.
Повний текст джерелаAudet, Jean-Nicolas. "Le bleu de méthylène comme traitement potentiel de sclérose latérale amyotrophique : étude de modèles murins surexprimant la superoxyde dismutase ou la TDP-43." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28925/28925.pdf.
Повний текст джерелаBucher, Thomas. "Transfert de gènes dans le système nerveux central d'un modèle félin de maladie du motoneurone." Nantes, 2013. https://archive.bu.univ-nantes.fr/pollux/show/show?id=85eedf7d-ea2c-4e3e-a562-2d012f9787ad.
Повний текст джерелаSpinal muscular atrophy (SMA) and amyotrophic lateral sclerosis are the most common motor neuron (MN) diseases characterized by the degeneration of the spinal cord MN, leading to often lethal progressive muscular atrophy, for which no cure is currently available. Among the most promising therapeutic approaches, a neuroprotective factor or a missing gene can be expressed or re-introduced in MN in a sustainable manner by gene therapy. Indeed, several studies have shown an unprecedented improvement of the lifespan of severe SMA mouse models after intravenous administrations of vector derived from adeno-associated virus serotype 9 (AAV9). However, before considering clinical application, efficiency and safety of such a strategy should be evaluated in large animal models, anatomically and physiologically more closely related to humans than rodents. The objective of this study was to test different strategies for gene transfer into the spinal cord of cats with a MN disease close to human type III SMA caused by the deletion of the LIX1 gene (limb expression 1). To identify an effective strategy for gene therapy in LIX1 cats spinal cord, we tested parallel to the intravenous administration of AAV9 vector, two AAV administration routes restricted to the central nervous system: intracerebral and intracisternal (in the cerebrospinal fluid) injections with two therapeutic transgenes candidates: the neuroprotective factor VEGF and the LIX1 gene. Our results showed that intracisternal injections of AAV9 lead to transgene expression in many MN throughout the spinal cord in both adult and newborn cats with limited peripheral transduction. This study could validate the use of intracisternal administration of AAV9 vectors in a therapeutic strategy for MN diseases in humans
Grondard, Clément. "Analyse des effets de l'exercice physique dans des modèles souris de maladies humaines sévères touchant le motoneurone." Paris 6, 2007. http://www.theses.fr/2007PA066146.
Повний текст джерелаKumar, Sunny. "Signatures moléculaires neuronales et effets de withanolides inhibiteurs de NF-kB chez des modèles de souris de la SLA et de démence fronto-temporale." Doctoral thesis, Université Laval, 2021. http://hdl.handle.net/20.500.11794/69127.
Повний текст джерелаBurg, Thibaut. "Détermination du rôle des neurones corticospinaux dans le déclenchement et la progression de la sclérose latérale amyotrophique chez les souris Sod1G86R." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ046.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) is a disease characterized by progressive and combined degeneration of corticospinal neurons (CSN) and bulbar and spinal motoneurons (MN). Studies in patients suggest a cortical origin and a corticofugal spread of the pathology. However, this hypothesis has never been demonstrated in ALS patients nor tested in mouse models. The work of this thesis allowed to test the role of subcerebral projection neurons (SCPN) in the onset and progression of ALS in Sod1G86R mice. To do so, we generated a new mouse model developing ALS in the absence of SCPN. Results show that the absence of SCPN delays the onset of the pathology, prolongs the survival of the animals, while reducing the decline of their motor abilities. These data suggest that the absence of SCPN is beneficial and that, in an ALS context, SCPN would be toxic and have a preponderant role in the onset and establishment of the pathology. This work shows the importance of including the CSN study for the development of future therapeutic strategies
Bertin, Eléonore. "Étude de l'augmentation du trafic en surface des récepteurs P2X4 de l’ATP à l’aide de nouveaux modèles murins transgéniques : implications dans les processus mnésiques et la sclérose latérale amyotrophique." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0341.
Повний текст джерелаATP signaling and surface P2X4 ATP-gated receptor channels are upregulated in various neurological disorders including amyotrophic lateral sclerosis (ALS), a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. P2X4 displays a widespread distribution in the central nervous system (CNS) neurons and glial cells as well as in multiple peripheral cell types throughout the body. A key question regarding the role of purinergic signaling in health and disease is the function of this upregulated surface P2X4 state observed in specific cell types.To elucidate the cell-specific functions of P2X4 in a pathological context, a conditional transgenic knock-in P2X4 mouse line (floxed P2X4mCherryIN) was created allowing the Cre activity-dependent genetic swapping of the internalization motif of P2X4 by the fluorescent protein mCherry to prevent constitutive endocytosis of P2X4. We describe and characterize two distinct knock-in mouse lines expressing non-internalized P2X4mCherryIN either in excitatory forebrain neurons (CamK2) or in all cells natively expressing P2X4 (CMV). The genetic substitution of wild-type P2X4 by non-internalized P2X4mCherryIN in both knock-in mouse models does not alter the sparse distribution and subcellular localization of P2X4 but leads to a cell-specific increased surface P2X4 expression mimicking the pathological upregulated P2X4 state. We provide evidence that the increase in P2X4 at the surface of excitatory neurons decreases anxiety and impairs memory processing due to alteration of synaptic plasticity in the hippocampal CA1 region.To unravel the implication of P2X4 in ALS pathogenesis, we generate innovating double transgenic mice called SOD1:P2X4KI and SOD1:P2X4KO using the new knock-in CMV mice model expressing the upregulated P2X4 receptor in all cells that expressed natively the P2X4 receptor (P2X4KI) or a trangenic mice lacking the P2X4 gene (P2X4KO) with most commonly used ALS model carrying the human SOD1-G93A mutation (SOD1). Interestingly, the ablation of the P2X4 gene as well as the expression of non-internalized P2X4 in SOD1 mice have a significant and positive impact on motor performances and animal survival revealing that P2X4 are active and complex players in ALS progression. In SOD1 mice spinal cord, the expression of P2X4 is initially restricted to MN and increased in microglia during the symptomatic phase of ALS, and P2X4 has a dual role on inflammation markers expression during the progression of the disease. In parallel, P2X4 surface expression significantly increased in peritoneal macrophages of SOD1 mice during ALS progression even from the presymptomatic stages suggesting that P2X4 may represent an early biomarker of ALS. Moreover, we reveal that the mechanism underlying the surface upregulation of P2X4 receptor in ALS models over the time can be explained by a competitive and progressive alteration of P2X4 constitutive internalization by SOD1 misfolded protein leading to MN death and associated neuroinflammation.Overall, we provide an innovative knock-in P2X4 model to study the functional contributions of upregulated P2X4 receptor in specific cells of the nervous system but also in peripheral tissues throughout the body that will be helpful for study many others pathologies besides ALS
Scekic-Zahirovic, Jelena. "Troncation conditionnelle de la protéine FUS chez la souris : un nouveau modèle animal du continuum sclérose latérale amyotrophique/démence fronto-temporale." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ002/document.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTLD) are now considered as a unique clinicopathological spectrum referred to as ALS/FTLD. Cytoplasmic aggregation of the physiologically nuclear FUS protein is a hallmark feature of a subset of ALS/FTLD. It remains unknonwn whether the critical pathogenic event relies on a loss of FUS normal nuclear functions, a toxic gain of function of FUS in the cytoplasm, or a combination of both.To answer this question we have generated a conditional mouse model expressing truncated FUS without nuclear localization signal - FusΔNLS. Our data showed that complete cytoplasmic mislocalization of truncated FUS protein within spinal motor neurons is a major determinant of motor neuron degeneration via toxic gain of function. A partial mislocalization of truncated FUS protein was sufficient to trigger key features of ALS and of FTLD.These studies allowed the elucidation of mechanisms underlying FUS role in ALS/FTLD, and will hopefully lead to development of therapies for these devastating diseases
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.
Повний текст джерелаMitochondria 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
Corbier, Camille. "Caractérisation d'un modèle murin knock out pour le gène C9orf72." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ080.
Повний текст джерелаAn 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
Zhu, Hongmei. "Prenatal dysfunctions of chloride-related inhibition in lumbar motoneurons of the SOD1G93A ALS." Electronic Thesis or Diss., Bordeaux, 2023. http://www.theses.fr/2023BORD0026.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) is a fatal and adult-onset neurodegenerative disease characterized by a progressive degeneration of motoneurons (MNs) with complex multifactorial aetiology. Most ALS studies have focused on symptomatic stages based on the hypothesis that ALS pathogenesis occurs when the disease becomes symptomatic. However, growing evidence indicates that ALS pathogenesis might start long before symptom onset. My PhD thesis work was based on the hypothesis that ALS - familial and sporadic - stems from deficits taking place during early development. With the aim of identifying early changes underpinning ALS neurodegeneration, the first part of my thesis analysed the GABAergic/glycinergic inhibitory postsynaptic currents (IPSCs) to embryonic (E) E17.5 MNs located in the ventro-lateral motor column from SOD1G93A (SOD) mice, in parallel with the analyse of chloride homeostasis. Our results showed that IPSCs are less frequent in SOD animals in accordance with a reduction of synaptic VIAAT-positive terminals in the close proximity of MN somata. SOD MNs exhibited an ECI 10 mV more depolarized than wild type (WT) MNs. This deficit in GABA/glycine inhibition was due to a reduction of the neuronal chloride transporter KCC2. SOD spontaneous IPSCs and evoked GABAAR-currents exhibited a slower decay correlated to elevated [Cl-]i. Using computer modelling approach, we revealed that the slower relaxation of synaptic inhibitory events acts as a compensatory mechanism to strengthen or increase the efficacy of GABA/glycine inhibition when ECI is more depolarized. Interestingly, simulations revealed an excitatory effect of low frequency (<50Hz) depolarizing GABA/glycine post-synaptic potentials (dGPSPs) in SOD-like MNs but not in WT-like littermates. At high frequency, dGPSPs switched to inhibitory effect resulting from the summation of the shunting components. The second part of my PhD thesis focussed on the effect of electrically evoked-dGPSPs, at different frequencies (7.5 to 100 Hz), on real lumbar E17.5 MNs in which a depolarized ECI (below spike threshold) was imposed. The aim was to examine whether the excitatory effect could be linked to morphological changes previously described in E17.5 SOD MNs. Results showed that some MNs were excited by low frequency dGPSPs and inhibited by high frequency dGPSPs (Dual MNs) and others were inhibited at all frequencies (Inhibited MNs). Dual effect was more often detected in SOD MNs. WT MNs were classified into two clusters according to their input resistance (Rin), Dual MNs being specific to high Rin and Inhibited MNs to low Rin. Morphometric data pointed out a reduced dendritic tree in high Rin WT Dual MNs and a large dendritic tree in low Rin Inhibited MNs. This was not the case in SOD MNs that were excited or inhibited whatever their morphology and Rin. In agreement with simulation showing that a less density of inhibitory current on MNs soma favours excitatory dGPSPs, we found less synaptic VIAAT terminals on the soma and proximal dendrites of SOD MNs, compared to littermate WT MNs, as well as a lower frequency of spontaneous dGPSPs. Altogether, my thesis data emphasize a prenatal defect in the CI- homeostasis and GABA/glycine innervation in the SOD1G93A ALS MNs. Before birth, a dominant population of MNs with low Rin emerges in WT animals. These MNs that are inhibited by dGPSPs could represent future ALS vulnerable fast MNs (putative FF). Interestingly, those MNs are not inhibited in SOD animals. The inhibitory dysfunction could be attributed to two distinct factors: morphology and perisomatic inhibitory synapse density. Of these two factors, the latter plays a major role by controlling capability of GABAergic/glycinergic neurons for shaping spinal motor output
Vaccaro, Alexandra. "Développement de modèles C. elegans de Sclérose Latérale Amyotrophique." Thèse, 2011. http://hdl.handle.net/1866/6925.
Повний текст джерелаTwo recently discovered causative genes for ALS, TDP-43 (TAR DNA Binding Protein 43) and FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) are under further investigation regarding their biological roles in neuropathies such as Amyotrophic Lateral Sclerosis (ALS). Since TDP-43 and FUS are evolutionarily conserved we turned to the model organism C. elegans to learn more about their biological functions. Here we report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response. We have generated mutant TDP-43 and FUS transgenic lines in C. elegans that recapitulate certain aspects of ALS including motor neuron degeneration and adult-onset paralysis. Proteotoxicity caused by ALS- associated mutations in TDP-43 or FUS also induce TDP-1 expression and consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild type TDP-1/TDP-43 by proteotoxicity may actively promote neurodegeneration. We also screened for small- molecule suppressors of mutant TDP-43 and FUS neuronal toxicity in transgenic C. elegans and identified methylene blue and salubrinal as potent suppressors of TDP-43 and FUS toxicity in our models through induction of the endoplasmic reticulum (ER) stress response. Our results indicate that protein folding homeostasis in the ER may be an important target for therapeutic development in neurodegenerative diseases.
Duhaime, Sarah. "Caractérisation de nouveaux modèles TDP-43/TDP-1 de Caenorhabditis elegans pour la maladie sclérose latérale amyotrophique." Thesis, 2020. http://hdl.handle.net/1866/25648.
Повний текст джерелаAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive and selective loss of motor neurons. ALS is incurable and there are no effective treatments available for people living with the disease. About 90% of the cases are sporadic whereas 10% are familial, and patients usually die two to five years after symptom onset. Many gene defects are associated with ALS, including mutations in genes encoding FUS, C9orf72, SOD-1 and TDP-43 proteins. We have developed a transgenic Caenorhabditis elegans model expressing human mutant TDP-43(Q331K) in GABAergic motor neurons. We have also obtained by mutagenesis and CRISPR-Cas9 physiologically accurate models based on mutations in tdp-1, the C. elegans ortholog of TARDBP. Our objective is to characterize these models and determine if they can recapitulate key aspects of the disease such as motor deficits and age-dependent neurodegeneration causing paralysis. We believe that the TDP-1 model will reflect more precisely the physiological expression of the gene in the human disease because of its mutation in an endogenous gene, the absence of overexpression and ubiquitous protein expression. Our results show that both TDP-43 and TDP-1 models have motor deficits, synaptic transmission impairments and age-dependent neurodegeneration. However, only the TDP-43 mutation seems to have an effect on lifespan. These models provide different physiological expression of mutant proteins and thus phenotypes of varying intensity levels. They will be useful tools to elucidate new pathogenic mechanisms of ALS as well as being good candidates for drug screening and developing therapeutic strategies.