Tesis sobre el tema "Chorée de Huntington – Génétique"
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Bourset, Jacques. "La chorée de Huntington : aspects génétiques actuels". Montpellier 1, 1990. http://www.theses.fr/1990MON11243.
Texto completoMasnata, Maria. "The prion-like properties of the mutant huntingtin protein : demonstration in in vitro and in vivo systems". Doctoral thesis, Université Laval, 2021. http://hdl.handle.net/20.500.11794/67993.
Texto completoHuntington’s disease (HD) is an autosomal dominant neurodegenerative disease that affects approximately 3 - 8 people in 100,000 individuals worldwide. HD is caused by a mutation in the HTT gene, which codes for the protein huntingtin (HTT), consisting of an expansion of 35 CAG repeats in the exon 1 of the gene and resulting in the elongated polyglutamine (polyQ) stretch at the N-terminal fragment of the protein HTT. Individuals who suffer from HD develop severe motor, cognitive and psychiatric impairments, which primarily manifest in adulthood. The onset of the disease is usually inversely proportional to the CAG repeat expansion, however, HD comes with a high variability of symptoms. HD is also associated with the expression of the mutated HTT (mHTT) protein. The mHTT protein adopts a pathogenic conformation, which accumulates in small and/or large cytotoxic aggregates. Although these events are suspected to contribute to neurodegeneration, the exact mechanisms underlying the pathophysiological pathways leading to disease onset and neuronal death are still under investigation. A growing body of evidence suggests that mHTT possesses prion-like capacities – the capacity to spread between cells and seed disease – a phenomenon associated with other proteins such as amyloid, tau and a-synuclein, all involved in various neurodegenerative diseases. We hypothesized that mHTT propagates in a non-autonomous manner and behaves in a prion-like fashion to influence the onset and severity of HD. To address this, exogenous synthetic mHTT fibrils were administered to several cell lines and to mice of different genetic backgrounds. Following an incubation period, the effects of mHTT fibrils on cellular viability, animal behavior and neuropathological features were examined. We observed that mHTT fibrils provoked cell death and morphological changes in cultured cells, induced transient HD-related behavioral phenotypes in healthy mice and exacerbated motor, anxiety-like and cognitive deficits in an HD mouse model. Our study suggests that extracellular mHTT can propagate between cellular elements and once uptaken, trigger pathological changes. In light of these observations, we believe that extracellular mHTT could represent an appealing target for future therapeutic strategies. Current disease-modifying treatments tested in the clinic are designed to target the HTT gene to decrease the expression of the protein, overlooking the mHTT load outside of the cell boundaries and/or which has accumulated in the system prior to the application of gene silencing/editing. Hence, a combinational therapy addressing both the intracellular and extracellular expression of mHTT could serve as a more global treatment of HD.
Ravache, Myriam. "Activation transcriptionnelle d'un répresseur de gènes neuronaux, NRSF, dans la maladie de Huntington : Identification des facteurs impliqués". Université Louis Pasteur (Strasbourg) (1971-2008), 2008. http://www.theses.fr/2008STR13167.
Texto completoHuntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotides, which code for polyglutamine expansions in the huntingtin (htt). Several physiopathological mechanisms have been proposed, including deregulated gene expression and can lead to the down-regulation of genes which are essential for neuronal morphology and function. NRSF, a transcription factor that plays a crucial role in controlling neuronal cell fate, by specifically inhibiting the expression of many neuronal genes, displays increased activity in HD which could explain the selective repression of neuronal genes. The goal of this work was to characterize the molecular mechanisms leading to NRSF activation in HD. In a cellular model, we show that the expression of mutant htt leads to increased NRSF expression by activating transcription from the NRSF promoter. We show that this transcriptional up-regulation does not involve two transcription factors known to be activated in HD: AP-1 and NF-KappaB. Finally, we demonstrate that Nrsf gene promoter is differentially regulated by two other transcription factors belonging to Sp family: Sp1 and Sp3, which act as transcriptional activator and repressor of the Nrsf gene promoter, respectively. Thus, we provide the first evidence that Sp factors regulate the transcriptional activity of Nrsf gene promoter. Our findings do not only allow the exploration of new mechanisms by which mutant htt activates the promoter of Nrsf gene, but they also open up fundamental new perspectives to understand the regulation of this gene, which is important during neuronal differentiation, and is deregulated in other disorders such as cancer
Delzor, Aurélie. "Développement de vecteurs lentiviraux pour surexprimer ou éteindre un gène dans le système nerveux central, application à la maladie de Huntington". Paris 6, 2012. http://www.theses.fr/2012PA066326.
Texto completoAbou-Sleymane, Gretta. "Polygluatamine expansion diseases : Transcriptional deregulations, alteration of the neuronal differentiation program and degeneration". Strasbourg 1, 2006. http://www.theses.fr/2006STR13209.
Texto completoHelmlinger, Dominique. "Identification des mécanismes de la toxicité induite par les expansions polyglutamines dans la rétine et étude du rôle de l'ataxine-7 dans la transcription". Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13201.
Texto completoBrule, Baptiste. "Caractérisation et modulation non pharmacologique des dérégulations épigénétiques associées à la maladie de Huntington : vers l’identification de nouvelles cibles thérapeutiques". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ015.
Texto completoHuntington's disease (HD) is a neurodegenerative genetic disease characterized by motor, cognitive, and psychiatric disorders caused by primary damage to the striatum. The pathogenic mechanism is complex and involve epigenetic and transcriptional dysregulations leading to a loss of neuronal identity and cell function. This thesis aimed to characterize the striatal epigenetic signature in mouse models with a celltype-specific resolution at different stages of HD. We observed that striatal neurons expressing the HD mutation undergo epigenetic erosion, reflecting accelerated aging in HD, induced by alterations in polycomb complexes. As epigenetic regulations are sensitive to the environment, we characterized the behavioral phenotype and molecular alterations of HD mouse model after housing in an enriched environment (EE) to decipher the epigenetic and transcriptomic effects induced by EE. Our findings thus provide a better understanding of early pathogenic mechanisms in HD, opening new therapeutic perspectives
Francelle, Laetitia. "A Study of Striatal Markers as Disease Modifiers in Huntington's Disease". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T070/document.
Texto completoHuntington’s disease (HD) is a neurodegenerative disorder caused by the mutation of huntingtin (Htt) gene, which leads to an abnormal polyglutamine expansion in the Htt protein.Whereas mutant Htt (mHtt) is ubiquitously expressed in the brain, it preferentially affects the striatum. Our hypothesis is that genes products selectively expressed in the striatum could be involved in the high vulnerability of the striatum. From this hypothesis, numerous teams studied “markers of the striatum”, that are genes product enriched in the striatum whose expression are up- or down-regulated in HD compared to healthy condition.During my thesis, I studied three of these striatal markers: the long intergenic non-coding RNA Abhd11os, and the two proteins µ-crystallin (CRYM) and doublecortin-like kinase 3 (DCLK3). A preliminary study from the laboratory has shown that these three markers have neuroprotective effects against a toxic fragment of mHtt in vivo. So, the aims of my thesis were to further characterize these three ill-defined disease modifiers and to better understand the putative molecular mechanisms underlying their neuroprotective effects against mHtt.I also conducted a translational study on DCLK3, whose results validate the high therapeutic potential of this protein.The elucidation of the mechanisms underlying the neuroprotective effects of these disease modifiers against mHtt toxicity will require further studies, but new trails can be envisioned, according to their characteristics. My study has enlightened new therapeutic targets and more globally gives an overview of molecular mechanisms to modulate to induce neuroprotective effects in this context, leading to new hypothesis explaining striatal vulnerability in HD
Lotz-Tavernier, Caroline. "Rôle des altérations transcriptionnelles et épigénétiques dans les déficits comportementaux de la maladie de Huntington". Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ099.
Texto completoHuntington's disease (HD) is a genetic neurodegenerative disease, characterized by motor, cognitive and psychiatric troubles, associated to transcriptional and epigenetic dysregulations, preferentially in the striatum. The causal relationship between these molecular dysfunctions and behavioral deficits is still poorly understood and its characterization is the objective of my thesis. We observed a progressive striatum-dependent procedural memory deficit in the R6/1 HD mouse, which is partially compensated by hippocampus-dependent spatial memory. Moreover, our transcriptomic data show that the cognitive deficit of R6/1 mice is correlated to altered striatal transcriptional regulations induced by procedural learning. Particularly, the expression of immediate early genes involved in neuronal plasticity is impaired. To improve these alterations, R6/1 mice were treated with a histone acetyltransferase activator. We observed a partial improvement of the procedural memory deficit of R6/1 mice. Surprisingly, this treatment induces transcriptomics and epigenetics changes, more particularly in the glial cells, and it improves cholesterol metabolism. Thus, our analyzes allows precisly, for the first time, to describe the relationship between the epigenetic, transcriptional and behavioral alterations in HD
Karam, Alice. "Retinal ciliopathies in Huntington's and SCA7 disorders". Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ069/document.
Texto completoPolyglutamine (polyQ) disorders are dominantly inherited neurodegenerative disorders caused by the expansion of CAG repeats translated into long polyQ tracts in the corresponding proteins. These diseases include Spinocerebellar ataxia 7(SCA7) and Huntington’s Disease (HD), caused by polyQ expansion ataxin-7 (ATXN7) and huntingtin (htt), respectively. SCA7 and HD mouse models develop similar retinopathies suggesting common pathomechanisms. In my thesis, I found that, in response to polyQ toxicity, SCA7 photoreceptors (PR) undergo several cell fates ranging from their deconstruction, to their migration and their death. Moreover, this cell death activates the proliferation of Müller glial cells and their differentiation into PR like cells. The pathomechanisms underlying HD and SCA7 are still unknown. Recently, I found that ATXN7 and htt are localized to the PR cilia and that the mutant proteins lead to a progressive loss of the wild-type proteins that correlates with defects in the PR cilia
Palfi, Stéphane. "Nouvelles approches thérapeutiques expérimentales pour le traitement des déficits moteurs et cognitifs de la maladie de Huntington". Paris 12, 1997. http://www.theses.fr/1997PA120054.
Texto completoCouette, Maryline. "Les troubles attentionnels dans la maladie de Huntington". Paris 6, 2010. http://www.theses.fr/2010PA066563.
Texto completoDavranche, Aurélien. "Étude des mécanismes moléculaires responsables des interactions aberrantes de la Huntingtine dans la maladie de Huntington". Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/DAVRANCHE_Aurelien_2010.pdf.
Texto completoHtt is a molecular interactions platform involved in critical cellular functions. The affinity of many Htt partners seems influenced by the polyQ size, thereby inducing cellular dysfunctions that could explain striatum-specific degeneration in HD. The molecular mechanism leading to these dysinteractions has never been studied in detail. It has been suggested, although not been proven so far, that mutant Htt adopts a specific stable conformation that would cause observed dysinteractions. However, the effects of the polyQ size on Htt/partners affinity have only been explored with semi-quantitative techniques, whose outcome could be influenced by the aggregation of studied proteins. We therefore hypothesized that the presence of aggregated fragments of Htt could perturb the Htt´s interactions. My main thesis project was to understand the molecular trigger of Htt's dysinteractions. I performed for the firsttime the precise quantification of Htt/partners affinity with a dedicated biophysical technique: the surface plasmon resonance. My results, obtained under strict control of the absence of aggregates, demonstrate that the affinity of Htt's partners is the same for wild-type and mutant Htt, excluding the conformational change model. Secondly, I demonstrate that the presence of aggregates dramatically influences Htt partner’s behaviour. Together, these results allow proposing a new model in which the aggregation process of the mutant protein is responsible for Htt dysinteractions. In addition, I took part in the characterization of a new Httpartner: the ryanodine receptor (RyR), a calcium channel
Gosset, Philippe. "Études de la propagation de la protéine huntingtine mutée". Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66687.
Texto completoHuntington's disease (HD) is a neurodegenerative disease caused by a mutation of the gene coding for the huntingtin protein (HTT). In its mutated form (mHTT), this essential protein forms into cellular aggregates, conferring toxicity to the new entity. HD is also characterized by marked neuronal death which underlies the motor, cognitive and psychiatric symptoms known to the pathology. The research project presented herein focused on investigating the ability of the mHTT to spread between cellular elements. This is part of a larger research program which proposes that HD may be, as other neurodegenerative diseases, a prion-like disorder. We therefore sought to determine whether the mHTT found in homogenates derived from postmortem brain tissue of HD patients can induce pathology after injection in different animal models. For this, we carried out three separate protocols: homogenates were injected into the brains of adult a) wild type and b) BACHD mice or c) non-human primates. The results of this study indicate that mHTT derived from post-mortem brain tissue of HD patients has a limited ability to spread between cells and does not represent prionlike characteristics. These observations contrast with previous work demonstrating that other forms of mHTT (fibrils, fibroblasts or induced pluripotent stem cells derived from HD cases) can indeed disseminate disease in a prion-like fashion as shown in various in vitro and in vivo models.
Mochel, Fanny. "Déficit énergétique dans la maladie de Huntington : outils diagnostiques et approches thérapeutiques". Paris 6, 2010. http://www.theses.fr/2010PA066311.
Texto completoMary, Véronique. "Modèles de chorée de Huntington chez le rat : activité du riluzole dans les modèles excitotoxiques". Paris 5, 1995. http://www.theses.fr/1995PA05P067.
Texto completoAviolat, Hubert. "Development of new high-throughput technology and combinatorial therapeutic strategy applicable to Huntington's disease and other amyloidoses". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ037.
Texto completoModulating amyloid proteins aggregation is therapeutically relevant (e.g. the familial amyloid polyneuropathy treated with Tafamidis). However, for many amyloidoses, there is yet no efficient aggregation modulator for therapy. It was recently shown that combining compounds that modulate the aggregation of amyloids can result in synergistic effects. A combinatorial screening strategy to identify synergistic cocktails of compounds could thus lead to a therapeutic break through for many amyloidoses. However, existing high-throughput technologies are not adapted for combinatorial screening.I developed SynAggreg - a very sensitive, accurate, reproducible, cost effective, flexible and high-throughput in vitro technology - which allows identifying both aggregation inhibitors and accelerators, characterizing their mechanism of action on aggregation kinetics and ranking them by their efficiency. SynAggreg is also the first technology suitable for combinatorial screening and for studying reliably synergistic effects of combinations of compounds. Finally, this new technology can be easily adapted to several amyloidoses by replacing the amyloid part of the fusion protein with molecular biology techniques. Thus, SynAggreg appears as a toolbox for fundamental and applied research, and has a high potential for valorization
Dufour, Josiane. "CRISPR/Cas9 pour traiter la maladie de Huntington". Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66699.
Texto completoHuntington’s disease (HD) is a neurodegenerative disorder characterized by a triad of motor, cognitive and psychiatric symptoms which results from an expansion of the CAG tract in the huntingtin gene. This mutation encodes for a longer polyglutamine stretch in the mutant huntingtin protein. Expression of the mutant protein eventually leads to cell dysfunction and death. OBJECTIVE: To this day, there is no disease-modifying therapy available for HD, but ongoing trials suggest that reducing the amount of the mutant protein could be beneficial. In this study we used the CRISPR/Cas9 system, a precise gene editing technology which can be directly employed with its partner enzyme, Cas9, to specifically target and correct genetic mutations, to shrink the causative mutation associated with HD. METHODS: A mice model of HD and littermate controls were aged to 12 months prior to undergoing stereotaxic intracerebral injections of AAV9 viruses containing either Cas9 D10A nickase and/or guide RNA (SgCTG/eGFP) targeted to the CAG expansion. Cognitive and motor testing were performed for 3 months after viral infection. Tissues and blood were collected at the completion of the protocol. Brain samples were analysed using immunofluorescence and western blotting to determine the degree of contraction achieved and the degree of expression and colocalization of GFP (guide RNA) and HA tags (Cas9D10A). RESULTS: Mild behavioural improvements were detected 3 months after co-administration of the two viral constructs to HD mice. Importantly, biochemical studies detected expression of both the guide RNA and the Cas9 in addition to a reduction in the amount of mHTT detected in HD mice receiving both viruses. CONCLUSION: CRISPR/Cas9 can be used to reduce the amount of mHTT and this is associated with improvements in cognitive and fine motor deficits. Further optimization of this technology could lead to a clinically relevant therapy.
Martin, Elodie. "Rôle de la protéine MSK-1 dans le remodelage de la chromatine et la neuroprotection dans un modèle murin de la maladie de Huntington". Paris 6, 2011. http://www.theses.fr/2011PA066354.
Texto completoRossignol, Julien. "Étude de la transdifférenciation nerveuse des cellules souches mésenchymateuses : application à la thérapie cellulaire restauratrice dans un modèle animal de la chorée de Huntington". Nantes, 2007. http://www.theses.fr/2007NANT2036.
Texto completoMesenchymal Stem Cells (MSCs) differentiate in cells from mesodermic and neuro-ectodermic lineages. MSCs as source of cells for restaurative cells therapy seems appropriate. On one hand, we characterized in vitro and studied MSCs transdifferentiation into nerve cells. On the other hand, MSCs were transplanted into the striatum of a 3NP-rat model of Huntington’s disease. This disease induces striatal GABAergic neuronal loss. Once MSCs transdifferentiated into GABAergic neurons they could, re-instate the lost function. The inflammatory response to Human or Rat MSC transplants was also investigated. In vitro, MSC transdifferentiation into neurons is difficult and depends on the culture conditions. After transplantation, no MSC transdifferentiation was observed but beneficial effects of the transplant were noticed. This recovery of function is certainly induced by the striatal release of trophic factors and/or extra-cellular matrix components by the MSCs. The inflammatory investigation performed after allo- or xeno-transplantation showed the absence of rejection after 90 days. Therefore an immuno-suppresive treatment would not be necessary for xenogeneic MSC transplantation. To conclude, MSCs could be a promissing cellular source as a treatment in neurodegenerative diseases. Rather than their transdifferentiative properties, their hypoimmunogenic capacity as well as their ability to produce trophic factors are of great interest
Cisbani, Giulia. "Cell replacement therapy for Huntington's disease : what we have learned from post-mortem analyses of grafted patients and mice models". Doctoral thesis, Université Laval, 2014. http://hdl.handle.net/20.500.11794/25302.
Texto completoHuntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disorder which manifests because of a mutation in the huntingtin gene. It is characterized by a variety of clinical signs which include psychiatric and cognitive problems as well as motor disabilities, in large part choreiform movements. Neuropathologically, the brains of patients afflicted with this disease present with a major atrophy of the cortex and striatum where massive cell losses are observed. To this day, cures remain unavailable and for this reason, an enormous amount of energy has been put into the development of experimental approaches, and for example into embryonic neuronal cell transplantation, which aims to replace lost cells. A few clinical trials have thus been initiated to evaluate whether such methodologies would be beneficial to patients. My PhD thesis focused, in large part, on the analysis of a number of brains from patients recruited for the University of South Florida trial and who eventually came to autopsy. These patients (4 analyzed post-mortem) received solid pieces of fetal striatal tissue and died between 9 and 12 years post-transplantation. Previous work carried out in Dr. Cicchetti’s laboratory has shown that graft survival is compromised in these patients long-term. The aim of my project was to further understand the mechanisms underlying this suboptimal graft survival. We hypothesized that 1) poor vascularization of the graft, 2) the method of transplantation (solid tissue vs. suspension cells) and 3) the potential presence of mutant huntingtin (mHtt) within the grafted tissue may all contribute to graft demise. Indeed, elements of the neurovascular unit were largely absent within the solid grafts. Grafts presented a lower density of capillaries and absence of large blood vessels compared to the host brain. Moreover, we observed a reduced number of astrocytes within the grafts and a limited interaction of these cells with blood vessels, suggesting impairment in blood brain barrier elements. The absence of astrocytes was accompanied by the lack of the gap junction subunit connexin 43, important for graft-host integration. Interestingly, when dissociated cells were transplanted in the striatum of YAC128 mice, a murine model of HD graft survival was excellent and neither the graft vascularization nor the interaction between astrocytes and vessels was altered. Finally, we describe for the first time the presence of mHtt inclusions within the grafted tissue. In the HD transplanted cases, aggregates were detected only in the extracellular matrix of the graft while in the host brain they co-localized with neurons or other cellular elements, such as the basal lamina of blood vessels. Taken together, this thesis sheds new light onto potential mechanisms contributing to poor long-term graft survival in HD patients. These results will help improve such therapies as well as to better understand disease process in HD.
Lauruol, Florian. "Étude des propriétés prioniques de la huntingtine mutée dans des modèles in vitro et in vivo". Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/35845.
Texto completoBoussicault, Lydie. "Déficits métaboliques dans la maladie de Huntington : rôle clef des interactions entre les neurones et les astrocytes". Paris 6, 2013. http://www.theses.fr/2013PA066056.
Texto completoImpaired brain energy metabolism in Huntington’s Disease: critical role of astrocyte-neuron interactions Huntington’s disease (HD) is a dominant inherited neurodegenerative disorder caused by a mutation within the gene encoding for Huntingtin protein (Htt). HD is characterized by motor and cognitive deficits and by cerebral energy metabolic alterations occurring even before symptoms onset. The purpose of our study was (1) to obtain a brain energy metabolic map of a transgenic mouse model of HD (BACHD mice) and (2) to characterize the respective roles of astrocytes and neurons in those metabolic deficits. Our study shows that BACHD mice, which develop a progressive HD, present localized metabolic alterations reminiscent of those observed in pre-symptomatic patients. In vitro experiments suggest that mHtt expression into astrocytes is necessary for the development of neuronal metabolic impairment. MHtt affects neuronal metabolism via a non cell-autonomous mechanism involving an increased oxidative stress
Ben-Haïem, Léa. "Etude de la protéolyse et de l'agrégation de la huntingtine,protéine mutée dans la maladie de Huntington". Université Louis Pasteur (Strasbourg) (1971-2008), 2005. https://publication-theses.unistra.fr/public/theses_doctorat/2005/BEN-HAIEM_Lea_2005.pdf.
Texto completoHuntington's disease (HD) is caused by the instable expansion of CAG triplet repeat in the huntingtin (htt) gene encoding for a polyglutamine (polyQ) expansion. One of the pathogenic mechanisms that are proposed for HD is the abnormal accumulation of htt cleavage products leading to dysfunction and neuronal cell death. Htt fragments are more toxic than htt full length and form intraneuronal inclusions. To determine how htt fragments are generated is essential to understand HD pathogenesis and to develop new therapies. Some studies have shown the involvement of caspases and calpains in htt proteolysis. I have participated to the idendification of 2 main htt cleavage products that build up differentially inclusions in HD brains, our cellular and rat model for HD. Then, I have tried to determine the cleavage sites leading to the production of theses fragments. We have defined one cleavage region and 2 approaches have been used to identify precisely the cleavage site. The interest region was limited to htt amino acids 110 to 117. I have shown in vitro that aspartyl proteases are involved in htt proteolysis. I have tested some candidate proteases and have shown that cathepsin D cleaves htt and produces the htt fragments in vitro. However, at least one other aspartyl protease cleaves htt in vivo. I have shown in our cellular model new htt aggregated cytoplasmic strtuctures that are different and seen earlier than cytoplasmic inclusions. I have also participated to the study of mutated ataxin-3 cleavage fragments. Mutated ataxin-3 is involved in SCA3. I have precised the epitope of the 1H9 antibody directed against ataxin-3. I have reduced the ataxin-3 cleavage region. Finally I have contributed to Rousseau et al's study showing that htt aggregation is specific to the nucleo-cytoplasmic compartment
Poreau, Brice. "Rôle de la huntingtine dans le muscle". Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV077/document.
Texto completoHuntington Disease (HD) is a rare multisystemic neurodegenerative genetic disorder, which combines psychiatric, cognitive and motor alterations. It is caused by an increase in CAG repeats in the huntingtin gene, resulting in an expansion of polyglutamine stretch in the protein. This induced a loss of the huntingtin protein (HTT) normal function associated with production of a mutant protein. HTT is an ubiquitous microtubules associated protein, with numerous functions among which vesicles and organelles traffic along microtubules. Along this line, one of its functions could be the traffic of reticulum vesicles to form contact point with the plasma membrane in neurons. Moreover, a phenocopy named Huntington’s disease like 2 is due to junctophilin-3 loss of function. Junctophilin 3 is involved in contact points between endoplasmic reticulum and plasma membrane in neurons. These studies are dedicated to the validation of the hypothesis of the role of HTT in contact points between endoplasmic reticulum and plasma membrane in another model, in which contacts between reticulum and plasma membrane are of major importance: the skeletal muscle cell. Indeed, the contact points between sarcoplasmic reticulum and plasma membrane (T-Tubule), called the triads, are the basis of excitation-contraction coupling in muscle. In these studies, we develop cellular and animals models with a loss of expression of HTT in skeletal muscle specifically. Theses studies show that calcium release is altered at the cellular level and muscle force is altered at animal model level. Theses alterations are correlated with loss of expression of the main receptors of the triad. Finally, fragment of the normal protein can restore calcium defects. Theses studies put forward the role of huntingtine in skeletal muscle
Ouary, Stéphane. "Évaluation du potentiel de la thérapie génique in vivo dans un modèle phénotypique de la maladie de Huntington chez le rongeur". Paris 12, 2001. http://www.theses.fr/2001PA120060.
Texto completoHuntington disease (HD) is a dominant transmission genetic and hereditary pathology whose target is central nervous system and mainly striatum. Onset of clinical symptoms (abnormal movements, cognitive alterations and psychiatric troubles) is about thirty and aiways Ieads to death. A phenotypic model has been developed in Sprague Dawley (SD) rats with 3NP intoxication, a succinate deshydrogenase inhibitor, but this strain was highly heterogeneous. In our experiments, Lewis rats were much more homogenous than SD rats with measurable motor deficits and related striatum systematic bilateral degeneration. As no treatment exists for HD, we have tested cerebral administration of genetica!Iy recombinant virus able to induce CNTF expression, a factor with a great survival potential in vitro and in vivo. Our resuits showed that motor performances cf 3NP intoxicated rats injected with AdenoCNTF were as good as sham ones and we noted a subsequent neuroprotection not only in striatum but equally in structures known to be connected to striatum such as premotor cortex or globus pallidus. As the same, we wanted to test lentiviral vector which is able to integrate CNTF gene in cellular DNA and induce long term expression. Ours resuits showed that motor performances cf 3NP intoxicated rats injected with LentiCNTF were as good as sham ones. Moreover, with striatal LentiCNTF injection, neuroprotection is observed not only in the striatum but in anatcmically linked structures such as globus pallidus. As a conclusion, either mediated adenoviral or lentiviral vector CNTF synthesis appears as a powerful mean to reduce neuronal degeneration and correlated abnormal movements in HD
Brisard, Luc. "Association d'une chorée et d'une acanthocytose : à propos d'une observation, revue de la littérature et discussion". Bordeaux 2, 1994. http://www.theses.fr/1994BOR2M210.
Texto completoGargiulo, Marcela. "Psychopathologie de la temporalite : medecine predictive, psychologie de l'anticipation : etude sur la qualite de vie d'une population a risque pour la maladie de huntington". Paris 7, 1999. http://www.theses.fr/1999PA070059.
Texto completoFerreri, Florian. "Marqueurs diagnostiques et pronostiques dans la schizophrénie : intérêt des signes neurologiques mineurs et des marqueurs lipidiques membranaires". Paris 6, 2012. http://www.theses.fr/2012PA066328.
Texto completoGodin, Juliette. "Maladie de Huntington : Dynamiques intracellulaires et voies de dégradation comme cibles thérapeutiques". Paris 11, 2009. http://www.theses.fr/2009PA11T025.
Texto completoSousa, Cristovao. "Huntington disease and breast cancer". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA114823/document.
Texto completoHuntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in the huntingtin (HTT) gene. The corresponding polyglutamine expansion in the HTT protein causes specific neuronal death, but the consequences of HTT mutation in other tissues are less well understood. Nevertheless, HD mutation causes peripheral symptoms as HTT is an ubiquitous protein. HD was associated to lower cancer incidence, however, the mechanisms behind this effect were not described. Here we have studied the role of wild-type and mutant HTT in breast cancer, where we found the protein to be highly expressed. We demonstrate that mouse breast cancer models (MMTV-PyVT and MMTV-ErbB2) expressing mutant HTT (knock-in mice carrying 111 CAGs) develop aggressive mammary tumors as compared to control mice. Epithelial-to-mesenchymal transition is enhanced with subsequent increased cell motility and metastasis. These tumors accumulate tyrosine-kinase receptor HER2 at the membrane, due to a dynamin-dependent endocytosis defect in the presence of mutant HTT. HER2 enhanced signaling is responsible for the aggressiveness of the mutant HTT expressing tumors, as demonstrated by Trastuzumab treatment, an antibody against HER2 that restores motility and invasion in tumor cells carrying HD mutation. The wild-type HTT has itself a protective role in cancer, inhibiting metastasis due to a possible role in cellular junction maintenance. Thus, our work unravels a key role of HTT in breast cancer progression, with the mutant HTT triggering the development of aggressive and metastatic tumors
Aubry, Laetitia. "Exploration du potentiel thérapeutique des cellules souches embryonnaires humaines pour la thérapie cellulaire de la maladie de Huntington". Thesis, Evry-Val d'Essonne, 2008. http://www.theses.fr/2008EVRY0027/document.
Texto completoHuntington’s disease (HD) is a neurodegenerative monogenic disorder resulting primarily in loss of GABAergic medium spiny striatal neurons (MSN). There is no known treatment to cure this pathology. Recent clinical trials consisting in transplanting human fetal tissue into the striatum of HD patients resulted in the substitution of lost cells and lead to functional benefits. However, application of this treatment to a large number of patients is restricted because the source and the processing of fetal cells are limiting factors. Thus, it is necessary to identify an alternative source of cells suitable to replace efficiently fetal tissue. Human embryonic stem (hES) cells, because they are self-renewable and pluripotent, are prime candidates. The aim of our work was to evaluate the therapeutic potential of hES cells for cell therapy of HD. We have designed a protocol to direct the differentiation of hES cells toward a striatal neuronal fate. This protocol allows the production from hES cells of striatal progenitors that are able to differentiate in MSN in vitro. Once transplanted into the lesioned striatum of rats these progenitors can survive and differentiate in MSN. On the other hand this xenografting experiments revealed that grafted cells have an extensive proliferation capacity. All the in vitro and in vivo data demonstrate that hES cells differentiation can be efficiently direct to a cell population relevant for cell therapy of HD. However these results underlines specific precautionary action on the path to the clinic, allowing for blocking cells proliferation if need be
Marelli, Cecilia. "Amélioration d'un composé actif contre la maladie de Huntington". Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT007.
Texto completoThe subject of this thesis is the further characterization and development in therapeutic purpose of P42 peptide in Huntington's disease. This peptide was previously identified in the team led by Florence Maschat and it showed be able to reduce the presence of aggregates in different cell models, but also Drosophila and murine (mouse R6 / 2) of Huntington's disease. P42 is also able to prevent neuronal degeneration and alteration of axonal transport in the tests performed in Drosophila (Arribat et al. 2013). Finally the motor abnormalities, weight loss and brain atrophy are ameliorated in vivo in R6 / 2 mice treated with P42. In the latter case, P42 was conjugated to TAT transducing peptide, derived from HIV, and was inserted into microemulsions, with the purpose of enabling repeated administrations of the peptide by intra-mucosal route, protect the peptide until his arrival to the brain and facilitate its diffusion through the membranes and the blood-brain barrier (Arribat et al. 2014). The efficacy of this peptide has been shown following administration in a pre-symptomatic stage; however, unpublished results also suggest a partial efficacy in post-symptomatic level. Thus this peptide would be through the inhibition of aggregation by interacting with Htt in its N-terminal part, and in particular at the N17 part. Preliminary results also suggest that, as part physiologically present in the Htt protein, P42 and could have a beneficial physiological role, particularly in terms of axonal transport, level of expression of Brain nerve factor (BDNF), and neuronal activity.My thesis consists of a hand on a laboratory work, and secondly on a work documentation. The laboratory work was conducted using the Drosophila model. In the first part I tried to better characterize the effectiveness of P42TAT and compare it to that of P42 in inhibiting aggregates in the salivary glands and in the protection of the degeneration of the eye. In particular, I tested the efficacy of oral administration of the peptide P42TAT on reducing aggregates in the salivary glands. In the second part I helped evaluate the effectiveness of a shorter fragment of P42, P42B; this peptide was first identified through studies on the degradation of P42TAT in extracts of brain by MALDI; this fragment of 14 aa was found after 3 h and therefore could be an active portion, sufficient for the effectiveness of the peptide. In the third part I contributed to studies to study the physiological role of P42 in axonal transport.The documentation work was finalized at the submission of a dossier to the European Agency for medicine (EMEA), in order to obtain for P42 the label of orphan drug for Huntington's disease. This result is particularly important and could be a first step in the clinical development of this peptide. Indeed no curative treatment exists to date for Huntington's disease and the ability to perform pre-symptomatic tests can provide a single window for early therapeutic intervention. Moreover, in recent years, clinical studies monitoring symptomatic and pre-symptomatic patients were conducted (PREDICT-HD studies and TRACK-HD), which led to the identification of biomarkers, in particular of imaging, able to follow the evolution of the disease, already at a pre-symptomatic stage, be used to objectively evaluate the effectiveness of treatment if available. Finally, all of this work has allowed me to gain expertise and to reflect on the use of peptides for therapeutic purposes in Huntington's disease, with the production of paper review on the subject submitted to an international journal
Boyer, Cécile. "Utilisation de rats transgéniques pour l'étude des pathologies neurodégénératives : maladies de Parkinson et de Huntington". Nantes, 2009. http://www.theses.fr/2009NANT2097.
Texto completoNeurodegenerative disorders such as Parkinson's (PD) and Huntington's diseases (HD) have in common to present no available curative treatment. Research on animal models is therefore essential to develop new therapeutic strategies and better understand the pathophysiological mechanisms of these diseases. Transgenic animals are more progressive models and are closer to human diseases than toxic models. Thus, we decided to develop a new model to study PD. Our transgenic rat expresses the gene for human α-synuclein double mutation (A30P and A53T) under the control of the promoter of the rat tyrosine hydroxylase. The characterization of this model showed a strong expression of the human α-syn in the olfactory bulbs correlated with olfactory deficits which appears as early as 6 months. We also note an expression of the α- syn in the substantia nigra and the locus coeruleus inducing some neurological and motor alterations from 16 months of age. In a second study, we wanted to compare the effect of transplantation of mesenchymal stem cells (MSCs) with those of fetal ganglionic eminence neuroblasts in a transgenic model of HD, the HD 51 – CAG rat. We have shown that only homozygous transgenic rats exhibited disturbances in motor and neurological tests. When symptoms were observed, only MSC transplantation was able to restore impaired functions. In conclusion, transgenic rats allow the studying of the progressive nature of neurodegenerative diseases which, in turn, permits the development of suitable therapies. The MSC transplantation seems to be a promising restorative therapy in neurodegenerative disorders
Eschbach, Judith. "Caractérisation de la fonction in vivo de la dynéine cytoplasmique par l'utilisation de souris mutantes". Strasbourg, 2011. http://www.theses.fr/2011STRA6137.
Texto completoCytoplasmic dynein is a molecular motor that drives cargoes, including whole organelles such as mitochondria, from the periphery of the cell to the perinuclear region by using microtubules as railroad tracks. In Neurons, Dynein is involved in retrograde axonal transport, which is a process required for neurons survival. Alterations in axonal transport, in both anterograde and retrograde axonal transport, were found in neurodegenerative diseases. This thesis work aims at showing that an axonal transport alteration is not sufficient to induce motor neuron disease (Dupuis, 2009), but sufficient to provoke a striatal dysfunction (Braunstein, 2010). Besides this neuronal aspect, dynein seems to be involved in lipids metabolism since dynein mutant mice present also a metabolic phenotype. Indeed, they showed an increase of fat mass in correlation with age due to a defective lipolysis associated with an increase oxidative stress (Eschbach, 2011). In parallel, we observed that dynein is required for the mitochondrial functions (manuscript ongoing). Finally, we determined the mechanisms of protective effect of dynein mutation in ALS mice (Fergani, 2011). In conclusion, this thesis work aims at showing that an axonal transport alteration is not sufficient to induce motor neuron disease, but sufficient to provoke a striatal dysfunction. Concerning the white adipose tissue, dynein seems to be involved in the lipolysis process. In addition, our results suggest that dynein is required for the mitochondrial function. Our current hypothesis is that this mitochondrial dysfunction could provoke the observed phenotype in both striatum and adipose tissue
Turgeon, Andréanne. "Caractérisation biochimique et immunohistochimique de la protéine Tau dans diverses tauopathies". Master's thesis, Université Laval, 2018. http://hdl.handle.net/20.500.11794/31451.
Texto completoMore than 25 million people worldwide are affected by different forms of dementia, the most known being Alzheimer’s disease (AD). This neurodegenerative disorder is characterized by the presence of β-amyloid plaques and neurofibrillary tangles formed by toxic aggregates of Tau protein. These aggregates are due to the hyperphosphorylation of this microtubule-associated protein, which destabilize its interaction with them and could participate to neuronal deterioration. To study Tau protein, many laboratories use animal models, and preparation methods of biological samples vary between each laboratory, which could potentially have effects on its observation. AD is the most common Tauopathy, a group of diseases expressing a pathological form of Tau protein. There are also secondary Tauopathies, where Tau pathology appears in late stages of the disease, such as Huntington’s disease (HD), with a Tau pathology that is not well characterized in humans. In this context, our hypotheses are that a better immunohistochemical and biochemical characterization of Tau protein is needed since methods currently used for its characterization are not optimal and that HD is indeed a secondary Tauopathy in human due to hyperphosphorylation of Tau and deficiency of splicing in advanced stage of the disease. Our objectives were to compare different preparation and fixation methods for the study of Tau protein by immunohistochemistry in mice models, and also to analyze phosphorylation and splicing levels of Tau protein in post-mortem brains of individuals with HD. Our results suggest that a fixation with Bouin, without perfusion and at 4°C would be the best method for the observation of Tau protein by immunohistochemistry, and that hyperphosphorylation and splicing impairments observed in individuals with HD allow to define this pathology as a secondary Tauopathy in humans.
Maxan, Alexander. "Mutant protein spread in Huntington's disease and its implications for other neurodegenerative disorders of the CNS". Doctoral thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66695.
Texto completoArribat, Yoan. "Caractérisation de P42, région cruciale pour la fonction de la Huntingtine et peptide capable d’inhiber la toxicité associée à la Chorée de Huntington". Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20140.
Texto completoHuntington's disease (HD) is a devastating and incurable neurodegenerative disorder. Aggregation processes of mutant Huntingtin (Htt PolyQ) play a central part in the pathology onset. In this context, recent studies pointed out the capacities of wild-type Huntingtin N-terminus to reduce both aggregation and toxicity associated with Htt PolyQ. The drosophila Homologue shares the sames properties. Basing on these observations, the present work realised a cut of human Huntingtin N-terminus in order to identify the region responsible for therapeutic benefits. This screen highlighted a 23 amino-acid sequence (noted P42), that inhibits Htt PolyQ aggregation in a HeLa cells model. Then, the protective effect of this peptide was confirmed in vivo, in a HD drosophila model.P42 therapeutic potential was explored in the R6/2 HD mouse model. The entry of the peptide into cells, was potentialised by grafting to P42, the transduction sequence of TAT. Then, the fusion protein P42-TAT was vectorised in microemulsion, in order to enhance the delivery of the peptide to the brain by resorting to a non-invasive administration way. This original protocol exhibited highly-significant rescues on behavioural, histological and molecular R6/2 phenotypes..Over the therapeutic aspect, P42 also represents an important region of Huntingtin. The study of this site led to a better understanding of Huntingtin physiological function. Biochemestrial experiments underlined the binding of Htt N-terminus on microtubules networks. This interaction depends on a range of complex processes (dimerization, cleavage) and suggests that the Huntingtin belongs to the family of Structual MAPs.In summary, the identification of P42 enhances the knowledge about Huntingtin function, and opens a new promising therapeutical avenue for HD
Teichmann, Marc. "Le rôle du striatum dans le traitement du langage". Paris 12, 2007. http://www.theses.fr/2007PA120055.
Texto completoWhile the linguistic role of cortical areas is well established, the role of subcortical structures, such as the striatum is still controversial. Based on linguistic claims that language processing implies both recovery of lexical information and the application of combinatorial rules, this thesis attempted to substantiate that the striatum is involved in linguistic operations pertaining to the latter component. In several studies with striatal-damaged patients, including more particulary Huntington's disease, we contrasted lexical abilities and rule application at different language levels (morphology, syntax, phonology) as well as in a non-linguistic domain, namely arithmetic. Two methodological approaches were used, comprising behavioural studies on the one hand, and brain-function correlations based on morphological and functional imagery on the other. My research showed that the striatum is involved in rule application at the morphological and syntactic level, and that this function extends to the domain of arithmetic. Furthermore, it suggested that the role in linguistic rule application is tied to ventral portions of the caudate and the putamen, while more dorsal portions of the striatum are involved in lexical operations. Finally, my findings showed that the striatum is part of a distributed cortical-sub-cortical network, subserving rule processing, and linking the caudate with portions of Broca's area. Based on these results I propose a functional model situating the striatum at the interface between rule and lexical representations that are thought to be integrated at the striatal level, which allows for the application of combinatorial language operations
Imbert, Marine. "Evaluation de différentes stratégies thérapeutiques antisens pour le traitement de la maladie de Huntington". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV044/document.
Texto completoHuntington’s disease (HD) is caused by a CAG repeat expansion in the exon 1 of huntingtin gene (htt), encoding for a mutant protein. It has been shown that the silencing/down regulation of huntingtin protein is a promising therapeutic lead. In this project, I have explored and compared three strategies using the antisense approach: a non-allele specific strategy, aiming to silence the global expression of htt; an allele specific strategy targeting CAG repeats to silence preferentially the mutant allele; and an exon-skipping strategy in order to remove cleavage sites which originally cause a shorter and toxic form of the htt protein. These strategies have been evaluated using two different tools: tricyclo-DNA (TcDNA), a new class of antisense oligonucleotides (AON) more efficient than the previous chemistries, and a vectorized approach using U7snRNA system allowing a stable expression of antisense sequences. Firstly, these different molecules have been assessed in vitro in HD fibroblasts quantifying mRNA and htt protein levels with RTqPCR and Western blot respectively. Subsequently, the most efficient sequences have been selected and intracerebroventricular (ICV) injections have been performed with corresponding AON and AAV-U7snRNA in a HD mouse model (YAC128). The most encouraging results have been obtained with the TcDNA-NS (for Non Specific allele), allowing a significant decrease of htt expression in cortex, hippocampus and striatum 2 and 6 weeks after ICV injection. These promising results suggest the potential of TcDNA as a new therapeutic tool for HD
El-Daher, Marie-Thérèse. "Huntingtin proteolysis and toxicity". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T029/document.
Texto completoHuntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in the N-terminus of the protein huntingtin (HTT). A crucial step in HD pathogenesis is the cleavage of full-length HTT into smaller N-terminal (N-ter) fragments that contain the polyQ stretch and that are toxic to neurons. HTT cleavage generates short N-ter fragments whose amino-acid positions range from 1-105 to 1-586. These fragments are observed in HD post mortem brain samples and their participation in neuronal death in HD is well characterized. During my PhD research, I investigated the consequences of full-length mutant HTT proteolysis by developing a time and site-specific controlled system for HTT proteolysis. I have assessed HTT cleavage on two sites caspase-6 and cathepsin Z. My results show that HTT cleavage induces neurotoxicity in vitro as well as in vivo, toxicity which depends on HTT proteolysis pattern. Briefly, we described an intramolecular interaction within the HTT domains which is impaired upon successive proteolysis of HTT. We found that HTT intramolecular interaction buffer mutant N-ter HTT-induced toxicity. Moreover, specific cleavages of the mutant HTT generated toxic N-ter fragments as they translocate into the nucleus. To conclude, my PhD work has shown that additional cleavage of mutant HTT induces cytotoxicity by different mechanisms
Fink, Kyle D. "Potentiel thérapeutique des cellules souches adultes pour le traitement de la maladie de Huntington". Nantes, 2013. https://archive.bu.univ-nantes.fr/pollux/show/show?id=dbc226c8-39fb-4920-b760-7f21b56c5e01.
Texto completoThe goal of this doctoral dissertation was to compare the potential therapeutic effects of transplanting various types of adult stem cells into the striata of R6/2 transgenic mice or rats given 3-nitropropionic acid (3-NP), which are commonly-used rodent models of Huntington's disease (HD). It was observed that transplants of mesenchymal stem cells (MSCs), isolated from bonemarrow and, to a more limited extent, umbilical cord blood, reduced behavioral and neuropathological deficits in R6/2 mice. Lt was hypothesized that these stem cell transplants exerted their beneficial effects through the release of neurotrophic factors and/or anti-inflammatory cytokines, rather than via cell replacement. In addition, it was found that intrastriatal transplants of induced pluripotent stem cells (iPSCs) reduced behavioral and neuropathological deficits in 3-Nptreated rats. In this latter study, it was observed that the iPSCs were able to differentiate into cells with region-specific neuronal phenotypes. It was hypothesized that mechanisms, other than primarily providing trophic support, may underlie the recovery observed in this second study. Taken together, the results from these two studies suggest that adult stem cells hold significant therapeutic potential for reducing behavioral deficits in HD
Brochier, Camille. "Analyse des transcriptomes du cerveau de souris : Mise en évidence de patrons régionaux d’expression conservés chez l’homme et altérés dans des modèles de maladies neurodégénératives". Paris 11, 2007. http://www.theses.fr/2007PA112123.
Texto completoIn order to get a better understanding of brain complexity at a molecular level, we explored the mouse brain transcriptome using the Serial Analysis of Gene Expression method. SAGE libraries were generated from 11 mouse brain territories, including six cortical regions, striatum, accumbens nucleus, thalamus, substantia nigra and ventral tegmental area. The entire project delivered 1. 2 million SAGE tags, allowing the detection of rare mRNAs. Comparison of all transcriptomes revealed 308 transcripts differentially expressed, a number of which have no documented function. We further analyzed the expression profiles by real-time RT-PCR or in situ hybridization (ISH). Since the brain is a heterogeneous organ, it was important to determine the cell types that are expressing the novel markers. A combination of in situ hybridization with immunohistochemistry showed the expression of 3 midbrain-enriched mRNAs in dopaminergic neurons. We tested whether mouse markers could be human markers. There was a good overall conservation of expression patterns in both species. To evaluate the assumption that genes predominantly expressed in a given brain structure may indeed be relevant to its function, we chose pathophysiological conditions that target specific neuron populations. Using quantitative RT-PCR, we so far measured the abundance of striatum- or cortex-enriched transcripts in the mouse R6/2 genetic model of Huntington’s disease. Likewise, we showed the regulation of transcripts enriched in the striatum or substantia nigra in pharmacological rodent models of Parkinson’s disease, in which the nigro-striatal dopaminergic pathway has been lesioned
Pouchot-Lermans, Catherine. "Un modèle de chorée de Huntington : étude électrophysiologique de la Pars reticulata de la substance noire et du noyau entopédonculaire chez le rat". Bordeaux 2, 1986. http://www.theses.fr/1986BOR22031.
Texto completoDelval, Arnaud. "Approche physiopathologique des troubles de locomotion dans la maladie de Huntington". Lille 2, 2007. http://www.theses.fr/2007LIL2S021.
Texto completoLepron, Evelyne. "Bases cérébrales de la communication inter-personnelle, empathie et émotion : applications à la maladie de Huntington". Toulouse 3, 2009. http://thesesups.ups-tlse.fr/618/.
Texto completoIn a world where social interactions are crucial, the brain allows us to feel what another person feels through neuronal resonance mechanisms, and to attribute thoughts and emotions to another person through regulation and metacognition mechanisms. Interpersonal communication deficits in Huntington's disease (HD) may originate from the alteration of these processes. We tried to answer the following questions. Which brain processes are involved when an individual responds inappropriately? How to explain the deficit of facial expressions recognition in HD? How do these patients process the association between social context and emotion? Are patients' spouses' empathy abilities also impaired? The experimental results showed that deal with a person who expresses an inappropriate facial affect modulates empathy processing at several levels. In particular, it recruits a network that supports metacognition and agentivity. Moreover, behavioral preparation related structures are inhibited when context and emotion are incongruent, which give evidence for the inability to react in such social situations. In MH, disorders of facial expression recognition cannot be attributed to the task difficulty. Rather, as for the lexical production impairment, it could be linked to a deficit in selection associated with a dysfunction of the anterior cingulate cortex. Besides, contrarily to controls, this structure is not inhibited, neither in patients nor their spouses, when faced the inadequate response of another person. We propose a model of context evaluation in empathy that includes the behavioral response, which is the ultimate goal of social interaction. The implications of these results are discussed in the framework of future research
Bédard, Catherine. "Innervation dopaminergique et sérotoninergique du striatum dans les maladies de Parkinson et d'Huntington". Master's thesis, Université Laval, 2010. http://hdl.handle.net/20.500.11794/21625.
Texto completoPéran, Patrice. "Traitement des verbes : Etude neuropsychologique dans les pathologies sous-corticales : étude de neuroimagerie fonctionnelle et pharmacologique chez des sujets sains". Toulouse 2, 2004. http://www.theses.fr/2004TOU20043.
Texto completoThe aim of this thesis is two-fold : 1) to characterize verb processing in relation to the fronto-striatal pathophysiology comparing noun- and verb- generation tasks in 34 non demented Parkinson's Disease (PD) patients, non demented and demented Huntington's Disease (HD) with matched control subjects 2) to assess, using fMRI, the effects of paroxetine on brain activity during language tasks related to action processing in healthy subjects after one-month treatment. 1) Our study evidences a clear language deficit in non-demented PD patients in tasks designed to explore verb processing. The profile of HD results is different since non demented and demented HD patients have showed a deficit whatever the task in comparison with control groups. 2) Our fMRI results show that paroxetine induces a relative enhancement of cortical activity for a low-level automatized language task, and a relative decrease of cortical activity for the two demanding tasks
Couly, Simon. "Analyse d'un peptide P42 protecteur de la maladie de Huntington". Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT022/document.
Texto completoHuntington’s disease (HD) is a rare genetic neurodegenerative disorder. Curative treatments are still actively sought. HD is induced by a mutation in the HTT gene inducing an abnormal expansion of the polyQ domain contained in the Huntingtin protein (Htt). Mechanisms and consequences of this mutation are now well described and allowed to identify an interaction of the Htt with the brain derived neurotrophic factor (BDNF) signaling pathway. BDNF is a neurotrophic factor, which plays important roles, through TrkB, one of its receptor, in neuronal development and plasticity. Mutant Htt (mHtt) down-regulates BDNF and TrkB transcription and transport along the axons.P42, a part of the Htt protein, is a 23aa peptide able to rescue HD pathological phenotypes, such as aggregation, axonal transport and neuronal viability.The aim of my PhD was to better understand the mechanisms of action of P42, in a purpose to optimize its therapeutic potential. To this end I developed different studies using different models.In a paper now accepted for publication in HMG, I first used a P42-based treatment on R6/2 HD mice, to analyze the effect of P42 on the BDNF/TrkB signaling pathway. To this end I analyzed pathologic phenotypes: behaviors or cell mechanisms developing in R6/2 mice and are related to the BDNF/TrkB pathway. I also measured BDNF and TrkB, mRNA or protein levels in both striatum and cortex. What I found is that P42 is acting on BDNF/TrkB pathway mainly by increasing the protein level of TrkB in the striatum.To observe the effect of P42 on vesicular transport, I rather used a Drosophila model, to perform live imaging based studies, in different transgenic conditions: with or without mHTT or P42.Also, in a way to better follow the progression of different pathological phenotypes and the effect of treatments on R6/2 mice, I benefited from a very recent and innovative tool, the HAMLET, which allows a multi-behavioral test.Finally, a bitherapy was used on R6/2 mice combining P42 and P3, a peptide raised against PolyQ mRNA that are also toxic.All those results contribute or will contribute to a better understanding of P42 mechanisms of action
Pépin, Jérémy. "Développement de l’imagerie métabolique par IRM-CEST : application à la maladie de Huntington". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS032/document.
Texto completoHuntington's disease (HD) is a inherited neurodegenerative disease affecting the brain. This disease is characterized by clinical symptoms such as psychiatric, cognitive and motor disorders worsening over time. These deficiencies are due to an abnormal increase in the size of the CAG repeats in the gene encoding the huntingtin protein. Thisaccumulates in the brain cells and causes their death. Previous studies have shown that the metabolic profile measured in ¹H NMR spectroscopy can be altered in patients with this disease as well as major atrophy of certain structures of the brain. Hypotheses involving defects in energy metabolism have been advanced to explain partially the pathophysiology of the disease. The metabolic actors could thus be biomarkers of interest. Using a promising MRI modality called Chemical Exchange Saturation Transfer (CEST), it is possible to detect low-concentrated labile protons that are classically undetectable in MRI. It thus becomes possible to map in vivo the distribution of metabolites such as glutamate (which is a neurotransmitter) or glucose (which is the fuel of cells) which are potentially involved in neurodegenerative diseases. The methodological developments carried out during this thesis were then applied to rodent models of Huntington's disease (KI140 mice, R6/1 mice, BACHD rats) in order to identify potential biomarkers of the pathology and to evaluate the relevance of these innovative MRI methods. All of these results and methods implemented during this thesis show the potential of CEST imaging for the study of neurodegenerative diseases