Immediate-early gene expression in structures outside the basal ganglia is associated to l-DOPA-induced dyskinesia.

International audienceLong-term l-3,4-dihydroxyphenylalanine (l-DOPA) treatment in Parkinson's disease (PD) leads to l-DOPA-induced dyskinesia (LID), a condition thought to primarily involve the dopamine D1 receptor-expressing striatal medium spiny neurons. Activation of the D1 receptor results in increased expression of several molecular markers, in particular the members of the immediate-early gene (IEG) family, a class of genes rapidly transcribed in response to an external stimulus. However, several dopaminoceptive structures in the brain that are likely to be affected by the exogenously produced DA have received little attention although they might play a key role in mediating those l-DOPA-induced abnormal behaviours. ΔFosB, ARC, FRA2 and Zif268 IEGs expression patterns were thus characterised, using unbiased stereological methods, in the whole brain of dyskinetic and non-dyskinetic rats to identify brain nuclei displaying a transcriptional response specifically related to LID. Within the basal ganglia, the striatum and the substantia nigra pars reticulata showed an increased expression of all four IEGs in dyskinetic compared to non-dyskinetic rats. Outside the basal ganglia, there was a striking increased expression of the four IEGs in the motor cortex, the bed nucleus of the stria terminalis, the dorsal hippocampus, the pontine nuclei, the cuneiform nucleus and the pedunculopontine nuclei. Moreover, the zona incerta and the lateral habenula displayed an overexpression of ΔFosB, ARC and Zif268. Among these structures, the IEG expression in the striatum, the bed nucleus of the stria terminalis, the lateral habenula, the pontine nuclei and the cuneiform nucleus correlate with LID severity. These results illustrate a global transcriptional response to a dyskinetic state in the whole brain suggesting the possible involvement of these structures in LID

Involvement of the bed nucleus of the stria terminalis in L-Dopa induced dyskinesia.

International audienceA whole brain immediate early gene mapping highlighted the dorsolateral bed nucleus of the stria terminalis (dlBST) as a structure putatively involved in L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesia (LID), the debilitating side-effects of chronic dopamine replacement therapy in Parkinson's disease (PD). dlBST indeed displayed an overexpression of ∆FosB, ARC, Zif268 and FRA2 only in dyskinetic rats. We thus hypothesized that dlBST could play a role in LID hyperkinetic manifestations. To assess the causal role of the dlBST in LID, we used Daun02 inactivation to selectively inhibit the electrical activity of dlBST ΔFosB-expressing neurons. Daun02 is a prodrug converted into Daunorubicin by ß-galactosidase. Then, the newly synthesized Daunorubicin is an inhibitor of neuronal excitability. Therefore, following induction of abnormal involuntary movements (AIMs), 6-OHDA rats were injected with Daun02 in the dlBST previously expressing ß-galactosidase under control of the FosB/ΔFosB promoter. Three days after Daun02 administration, the rats were tested daily with L-Dopa to assess LID. Pharmacogenetic inactivation of ∆FosB-expressing neuron electrophysiological activity significantly reduced AIM severity. The present study highlights the role of dlBST in the rodent analog of LID, offering a new target to investigate LID pathophysiology

Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species.status: publishe

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson’s disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptom