Dopamine | EPFL Graph Search

La dopamine (DA) est un neurotransmetteur, une molécule biochimique qui permet la communication au sein du système nerveux, et l'une de celles qui influent directement sur le comportement. La dopamine renforce les actions habituellement bénéfiques telles que manger un aliment sain en provoquant la sensation de plaisir ce qui active ainsi le système de récompense/renforcement. Elle est donc indispensable à la survie de l'individu. Plus généralement, elle joue un rôle dans la motivation et la prise de risque chez les mammifères, donc chez l'être humain aussi. La dopamine affecte aussi l'appétence des insectes, notamment des drosophiles et des abeilles domestiques. Cette molécule appartient au groupe des catécholamines, et est issue de deux acides aminés tyrosine ou phénylalanine. Dans le système nerveux central, elle active les récepteurs dopaminergiques postsynaptiques et présynaptiques (autorécepteur D2). Elle est principalement produite dans la substance noire et dans

A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions

Vignayanandam Ravindernath Muddapu

In order to understand the link between substantia nigra pars compacta (SNc) cell loss and Parkinson's disease (PD) symptoms, we developed a multiscale computational model that can replicate the symptoms at the behavioural level by incorporating the key cellular and molecular mechanisms underlying PD pathology. There is a modelling tradition that links dopamine to reward and uses reinforcement learning (RL) concepts to model the basal ganglia. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it in the RL-based behavioural model, which simulates the arm reaching task. Our results successfully replicated the impact of SNc cell loss and levodopa (L-DOPA) medication on reaching performance. It also shows the side effects of medication, such as wearing off and peak dosage dyskinesias. The model demonstrates how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD. It was able to predict the optimum L-DOPA medication dosage for varying degrees of cell loss. The proposed model has a potential clinical application where drug dosage can be optimised as per patient characteristics.

FRONTIERS MEDIA SA2022

DJ-1 as a neuroprotective protein in models of Parkinson's disease

Katarzyna Piorkowska-Stanco

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by the combination of motor symptoms like bradykinesia, tremor, rigidity and postural instability. The pathology of PD is related to the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) leading to the deficiency of dopamine in the striatal projection areas of these neurons. The pathogenesis of PD is not fully elucidated yet, however there is strong evidence that protein aggregation, mitochondrial dysfunction and oxidative stress play a primary role in the etiology of the disease. Most of PD cases are sporadic, however, several genes have been characterized to cause familial forms of the disease. Among them, mutations in DJ-1 were identified in families with autosomal-recessive early-onset PD and account for 2% of inherited PD cases. The DJ-1 protein was identified as an important player in cellular defense against oxidative stress as it possibly acts as an oxidative stress-induced chaperone and inhibits the formation of inclusions of α-synuclein, another protein related to PD. Alpha-synuclein mutations cause an autosomal dominant form of the disease. Moreover, this protein is a main component of Lewy Bodies, a pathological hallmark of PD. The goal of the experiments during my thesis was to investigate the potential protective effect of DJ-1 in toxin-based [6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)] as well as genetic models of PD in vivo. Towards this goal, the DJ-1 protein was over-expressed in rodent SNpc through the injections of recombinant adeno-associated viral vector (rAAV). In the first study, the DJ-1 over-expression led to significant protection of dopaminergic cells and spontaneous motor behavior in 6-OHDA-lesioned animals. However, this effect of DJ-1 was not confirmed when DJ-1 was over-expressed in the brains of mice lesioned with MPTP. In the third part of the study, the nigral over-expression of mutated a-synuclein (A30P mutation found in familial PD cases) was chosen as the genetic model of PD, already developed in our lab. Interestingly, significant preservation of spontaneous behavior was obtained when a-synuclein (A30P) was co-injected with DJ-1. However, this was accompanied by a modest protection of dopaminergic cells, suggesting the implication of other, subtle mechanisms regulating DJ-1-related basal ganglia output. Although the DJ-1 protection of dopaminergic cells was not always achieved, the effect of DJ-1 on the spontaneous behavior implies the interesting capacity of this protein. Our results suggest that DJ-1 is one of key factors playing role in maintenance of dopaminergic function. For a possible clinical application, DJ-1 may have to be linked with another neuroprotecting factor to assure a stronger protection effect.

EPFL2007

Dopaminergic fiber protection and regeneration by Wlds protein and GDNF in rodent models of Parkinson disease

Ali Etemad-Sajadi

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The resulting failure of the nigrostriatal pathway leads to profound dopamine deficiency, causing bradykinesia, tremor, rigidity and postural imbalance. The current therapeutic options for this disabling disorder remain symptomatic and are devoid of any impact on the neurodegeneration process per se. The development of neuroprotective and regenerative strategies constitute therefore an important challenge, in order to halt and possibly reverse the loss of the nigrostriatal pathway in PD. In the present study, we have investigated two different approaches to protect or restore the nigrostriatal dopaminergic system in rodent models of PD. In the first part, we examined the potential of a spontaneous dominant mutation in mice called slow Wallerian degeneration (Wlds) to confer protection of the dopaminergic pathway against the catecholaminergic toxin 6-hydroxydopamine (6-OHDA). Interestingly, the Wlds fusion protein proved capable to provide functional preservation of the nigrostriatal dopaminergic terminals. The observed Wlds-mediated protection of dopaminergic axons might help to further elucidate the mechanisms leading to the loss of dopamine axons in PD and conduct to the development of new therapeutic modalities for this disorder. In the second approach, we assessed the protective and regenerative potential of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) delivered via capsules in a rat model of PD. GDNF delivery by encapsulated cells resulted in regeneration of dopaminergic fibers and behavioral improvement in a bilateral 6-OHDA model in the rat. Importantly, GDNF withdrawal did not affect the morphological and behavioral effects in our model. The sustainability of the striatal dopaminergic reinnervation and behavioral performances following GDNF washout has important implications. It suggests that GDNF needs to be delivered only transiently to allow prolonged functional regenerative effect, rendering the retrievable capsules attractive to achieve this purpose in PD patients. The promising potential of GDNF to protect and regenerate the nigrostriatal pathway has been hampered by several recent studies showing that long-term GDNF overexpression in the intact nigrostriatal pathway induces a downregulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. In the last part of this work, we aimed therefore at investigating the effect of GDNF on other enzymes of dopamine biosynthesis, using a lentiviral vector-mediated gene transfer technique, in order to overexpress GDNF in rat striatum. We showed that in addition to TH downregulation, long-term GDNF overexpression results in tetrahydrobiopterin upregulation, and importantly in dopamine decrease in the intact striatum of rats. In a clinical perspective, dose and treatment duration of the trophic factor will thus have to be established and optimized with the aim of achieving beneficial neuroprotective effects while circumventing undesirable pharmacologic effects on dopamine biosynthesis. The discovery of new protective molecules such as the Wlds protein, as well as a better understanding of cellular effects of the promising neurotrophic factor GDNF might lead to the establishment of neuroprotective and neuroregenerative strategies for PD in the close future.

EPFL2005