9 research outputs found
Les systÚmes monoaminergiques : implication dans la physiopathologie et la thérapie de la maladie de Parkinson
Parkinsonâs disease is characterized by the manifestation of motor symptoms mostlyassociated with the degeneration of dopaminergic neurons. While Parkinsonâs disease is oftenfocused on motor deficits, the disease is also characterized by non-motor deficits, includinganxiety and depression, which are under studied and consequently are not well treated.Whereas some clinical studies suggested that anxiety and depression could be linked to thedegeneration of dopaminergic neurons, others suggested the involvement of norepinephrineand serotonin in the observed symptoms and also in the efficacy of Levodopa and deep brainstimulation of the subthalamic nucleus.In a first time, we investigated the respective role of the neuronal degeneration of dopamine,noradrenaline and serotonin in the manifestation of motor and non-motor parkinsonian-likedisorders in the rat. Our results demonstrate that despite the importance of the dopaminergicsystem, the disturbances in the three-monoaminergic systems play a key role in themanifestation of motor and non-motor deficits.In a second time, we studied the impact of monoamine depletions on the efficacy ofantiparkinsonian treatments, the Levodopa and deep brain stimulation of the subthalamicnucleus. Our results showed that the combined depletions could deteriorate the efficacy of theLevodopa and of the deep brain stimulation on some deficits. Together, these results canexplain the lack of efficacy of the antiparkinsonian treatments in some patients and thedifficulty to treat all the symptoms.Finally, we investigated the link between the subthalamic nucleus, which is an excitatorystructure of the basal ganglia, and the motor deficits, as well as the involvement of thebasolateral amygdala and the lateral habenula in emotional control of the behavior, and nonmotordeficits. We showed the parallel between changes in the neuronal activity of thesubthalamic nucleus and the motor deficits, of the basolateral amygdala and anxiety and ofthe lateral habenula and depression.Results from this thesis provide new evidences on the involvement of the threemonoaminergicsystems in the pathophysiology and the therapy of Parkinsonâs disease.La maladie de Parkinson est caractĂ©risĂ©e par la manifestation de symptĂŽmes moteursprincipalement dus Ă la dĂ©gĂ©nĂ©rescence du systĂšme dopaminergique. MalgrĂ© l'accent mis surles dĂ©ficits moteurs, la maladie de Parkinson est Ă©galement caractĂ©risĂ©e par des symptĂŽmesnon moteurs, incluant l'anxiĂ©tĂ© et la dĂ©pression, qui sont sous-Ă©tudiĂ©s et de ce fait pas bientraitĂ©s. Alors que certaines Ă©tudes cliniques ont suggĂ©rĂ© que l'anxiĂ©tĂ© et la dĂ©pressionpourraient ĂȘtre associĂ©es Ă la dĂ©gĂ©nĂ©rescence des neurones dopaminergiques, d'autres ontsuggĂ©rĂ© l'implication de la dĂ©gĂ©nĂ©rescence des neurones noradrĂ©nergiques etsĂ©rotoninergiques dans les troubles observĂ©s mais Ă©galement dans les effets induits par laLĂ©vodopa et la stimulation cĂ©rĂ©brale profonde du noyau sous-thalamique.Dans un premier temps, nous avons Ă©tudiĂ© le rĂŽle respectif de la dopamine, de lanoradrĂ©naline et de la sĂ©rotonine dans la manifestation des dĂ©ficits parkinsoniens moteurs etnon moteurs chez le rat. Lâensemble de nos rĂ©sultats dĂ©montre que malgrĂ© lâimportance dusystĂšme dopaminergique, la perturbation des trois systĂšmes monoaminergiques joue un rĂŽleimportant Ă la fois dans la manifestation des troubles moteurs et non moteurs.Nous avons Ă©galement Ă©tudier lâimpact des monoamines sur lâefficacitĂ© des traitementsantiparkinsoniens, Ă savoir, la LĂ©vodopa et la stimulation cĂ©rĂ©brale profonde du noyau sousthalamique,sur les troubles observĂ©s. Nos rĂ©sultats montrent que la dĂ©plĂ©tion combinĂ©e dessystĂšmes monoaminergiques peut altĂ©rer lâefficacitĂ© de la LĂ©vodopa ainsi que de lastimulation cĂ©rĂ©brale profonde sur certains troubles. Ces rĂ©sultats peuvent expliquer lemanque dâefficacitĂ© des traitements antiparkinsoniens chez certains patients et la difficultĂ© Ă traiter tous les symptĂŽmes.Pour finir, nous avons voulu mettre en Ă©vidence le lien entre le noyau sous-thalamique,structure excitatrice des ganglions de la base et les troubles moteurs, ainsi que lâamygdalebasolatĂ©rale et lâhabĂ©nula latĂ©rale, structures impliquĂ©es dans les comportements Ă©motionnels,et les troubles non moteurs. Nous avons mis en Ă©vidence le parallĂšle existant entre lesmodifications du mode de dĂ©charge des neurones du NST et les troubles moteurs, leschangements de lâamygdale basolatĂ©rale et les troubles anxieux ainsi que ceux de lâhabĂ©nulalatĂ©rale et les troubles dĂ©pressifs.Les rĂ©sultats de ces travaux de thĂšse ont donc permis dâapporter de nouvelles Ă©vidences surlâimplication des trois systĂšmes monoaminergiques dans la physiopathologie et la thĂ©rapie dela maladie de Parkinson
Monoaminergic systems : involvement in the pathophysiology and therapy of parkinsonâs disease
La maladie de Parkinson est caractĂ©risĂ©e par la manifestation de symptĂŽmes moteursprincipalement dus Ă la dĂ©gĂ©nĂ©rescence du systĂšme dopaminergique. MalgrĂ© l'accent mis surles dĂ©ficits moteurs, la maladie de Parkinson est Ă©galement caractĂ©risĂ©e par des symptĂŽmesnon moteurs, incluant l'anxiĂ©tĂ© et la dĂ©pression, qui sont sous-Ă©tudiĂ©s et de ce fait pas bientraitĂ©s. Alors que certaines Ă©tudes cliniques ont suggĂ©rĂ© que l'anxiĂ©tĂ© et la dĂ©pressionpourraient ĂȘtre associĂ©es Ă la dĂ©gĂ©nĂ©rescence des neurones dopaminergiques, d'autres ontsuggĂ©rĂ© l'implication de la dĂ©gĂ©nĂ©rescence des neurones noradrĂ©nergiques etsĂ©rotoninergiques dans les troubles observĂ©s mais Ă©galement dans les effets induits par laLĂ©vodopa et la stimulation cĂ©rĂ©brale profonde du noyau sous-thalamique.Dans un premier temps, nous avons Ă©tudiĂ© le rĂŽle respectif de la dopamine, de lanoradrĂ©naline et de la sĂ©rotonine dans la manifestation des dĂ©ficits parkinsoniens moteurs etnon moteurs chez le rat. Lâensemble de nos rĂ©sultats dĂ©montre que malgrĂ© lâimportance dusystĂšme dopaminergique, la perturbation des trois systĂšmes monoaminergiques joue un rĂŽleimportant Ă la fois dans la manifestation des troubles moteurs et non moteurs.Nous avons Ă©galement Ă©tudier lâimpact des monoamines sur lâefficacitĂ© des traitementsantiparkinsoniens, Ă savoir, la LĂ©vodopa et la stimulation cĂ©rĂ©brale profonde du noyau sousthalamique,sur les troubles observĂ©s. Nos rĂ©sultats montrent que la dĂ©plĂ©tion combinĂ©e dessystĂšmes monoaminergiques peut altĂ©rer lâefficacitĂ© de la LĂ©vodopa ainsi que de lastimulation cĂ©rĂ©brale profonde sur certains troubles. Ces rĂ©sultats peuvent expliquer lemanque dâefficacitĂ© des traitements antiparkinsoniens chez certains patients et la difficultĂ© Ă traiter tous les symptĂŽmes.Pour finir, nous avons voulu mettre en Ă©vidence le lien entre le noyau sous-thalamique,structure excitatrice des ganglions de la base et les troubles moteurs, ainsi que lâamygdalebasolatĂ©rale et lâhabĂ©nula latĂ©rale, structures impliquĂ©es dans les comportements Ă©motionnels,et les troubles non moteurs. Nous avons mis en Ă©vidence le parallĂšle existant entre lesmodifications du mode de dĂ©charge des neurones du NST et les troubles moteurs, leschangements de lâamygdale basolatĂ©rale et les troubles anxieux ainsi que ceux de lâhabĂ©nulalatĂ©rale et les troubles dĂ©pressifs.Les rĂ©sultats de ces travaux de thĂšse ont donc permis dâapporter de nouvelles Ă©vidences surlâimplication des trois systĂšmes monoaminergiques dans la physiopathologie et la thĂ©rapie dela maladie de Parkinson.Parkinsonâs disease is characterized by the manifestation of motor symptoms mostlyassociated with the degeneration of dopaminergic neurons. While Parkinsonâs disease is oftenfocused on motor deficits, the disease is also characterized by non-motor deficits, includinganxiety and depression, which are under studied and consequently are not well treated.Whereas some clinical studies suggested that anxiety and depression could be linked to thedegeneration of dopaminergic neurons, others suggested the involvement of norepinephrineand serotonin in the observed symptoms and also in the efficacy of Levodopa and deep brainstimulation of the subthalamic nucleus.In a first time, we investigated the respective role of the neuronal degeneration of dopamine,noradrenaline and serotonin in the manifestation of motor and non-motor parkinsonian-likedisorders in the rat. Our results demonstrate that despite the importance of the dopaminergicsystem, the disturbances in the three-monoaminergic systems play a key role in themanifestation of motor and non-motor deficits.In a second time, we studied the impact of monoamine depletions on the efficacy ofantiparkinsonian treatments, the Levodopa and deep brain stimulation of the subthalamicnucleus. Our results showed that the combined depletions could deteriorate the efficacy of theLevodopa and of the deep brain stimulation on some deficits. Together, these results canexplain the lack of efficacy of the antiparkinsonian treatments in some patients and thedifficulty to treat all the symptoms.Finally, we investigated the link between the subthalamic nucleus, which is an excitatorystructure of the basal ganglia, and the motor deficits, as well as the involvement of thebasolateral amygdala and the lateral habenula in emotional control of the behavior, and nonmotordeficits. We showed the parallel between changes in the neuronal activity of thesubthalamic nucleus and the motor deficits, of the basolateral amygdala and anxiety and ofthe lateral habenula and depression.Results from this thesis provide new evidences on the involvement of the threemonoaminergicsystems in the pathophysiology and the therapy of Parkinsonâs disease
Serotonergic neurons mediate the anxiolytic effect of L-DOPA: Neuronal correlates in the amygdala
Targeting α-synuclein for PD Therapeutics: A Pursuit on All Fronts
International audienceParkinson's Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time
In vivo validation of a new portable stimulator for chronic deep brain stimulation in freely moving rats
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An Embedded Deep Brain Stimulator for Biphasic Chronic Experiments in Freely Moving Rodents
Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy
International audienceThe synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinsonâs disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals
Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons
International audienceThe conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe thioflavin T (ThT). We report that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (Ïâ). The generation of Ïâ fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular corte
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CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation