Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg66/66 ) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg66/66 mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg66/66 mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

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Stress during pregnancy alters dendritic spine density and gene expression in the brain of new-born lambs

Remerciements :INRA, UE0332 BOURGES Domaine Expérimental Bourges-La SapinièreRodent studies show how prenatal stress (PS) can alter morphology in the cortico-limbic structures that support emotional and cognitive functions. PS-induced alteration is less well described in species with a gyrencephalic brain and complex earlier fetal development, and never in sheep at birth to rule out postnatal environment effects or influences of maternal behavior. This study aimed to assess the consequences of a mild chronic stress in pregnant ewes on the neurobiological development of their lambs at birth. During the last third of gestation, 7 ewes were exposed daily to various unpredictable and negative routine management-based challenges (stressed group), while 7 other ewes were housed without any additional perturbation (control group). For each group, a newborn from each litter was sacrificed at birth to collect its brain and analyze its expression levels of genes involved in neuronal dendritic morphology (Dlg4, Rac1, RhoA, Doc2b), synaptic transmission (Nr1, Grin2A, Grin2B) and glucocorticoid receptor (Nr3C1) in hippocampus (HPC), prefrontal cortex (PFC) and amygdala (AMYG). Results revealed that lambs from stressed dam (PS lambs) showed under-expression of Rac1 and Nr1 in PFC and overexpression of Dlg4 in AMYG compared to controls. To assess the morphological consequences of gene dysregulations, the dendritic morphology of pyramidal neurons was explored by Golgi–Cox staining in HPC and PFC. PS lambs had higher dendritic spine density in both structures and more stubby-type spines in the CA1 area of HPC than controls. This is the first demonstration in sheep that PS alters fetal brain, possibly reflecting functional changes in synaptic transmission to cope with adversity experienced in fetal life

OXIDATIVE STRESS AND MITOCHONDRIAL DYNAMICS MALFUNCTION ARE LINKED IN PELIZAEUS-MERZBACHER DISEASE

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Dossier • Pourquoi existe-t-il des différences entre les techniciens viticoles et les viticulteurs en ce qui concerne la protection face aux pesticides ? Le travail présenté ici s’efforce de comprendre leurs stratégies prudentielles. • Les coûts des produits phytosanitaires en grande culture sont variables selon les exploitations. La méthode de la régression quantile est appliquée ici pour faire l’évaluation de ces coûts en fonction de différents facteurs de variation des caractéristiques des exploitations. • La modulation de l’application des fongicides sur un système de culture céréalier est-elle rentable ? Cette question est étudiée par la comparaison des marges directes sur des exploitations de superficie croissante en Haute Normandie. • Les pratiques phytosanitaires en agriculture conduisent-elles à des tensions irréductibles avec l’environnement ? Une étude en Midi-Pyrénées montre l’émergence d’arguments sanitaires et commerciaux face à la persistance des logiques agricoles pour expliquer la diffusion de pratiques alternatives. • Y a-t-il des dynamiques environnementales liées à la territorialisation des MAE ? Une réponse est donnée ici dans trois régions du Sud-Ouest à partir de l’étude de projets MAET à enjeu eau et de l’évaluation des MAE précédentes. • Quel est le rôle de l’apprentissage collectif sur la réduction des risques liés à l’adoption des pratiques agricoles alternatives ? Des MAET-DCE portées par une coopérative sont étudiées pour analyser les modalités de la transmission de l’information technique. • Quelle est l’efficacité des mesures agro-environnementales pour réduire les pollutions diffuses des eaux de surface par les pesticides ? Une analyse coût-efficacité par le modèle SWAT est appliquée dans le bassin du Gers pour comparer différentes MAE. Faits et chiffres • L’augmentation du prix des engrais au cours des dernières années suscite de nombreux débats. L'article évalue le niveau de dépendance des exploitations agricoles européennes et françaises aux engrais. Note de lecture • Le défi de la diversification des entreprises agricole

A Polyphonic Marketplace: Images of EU External Energy Relations in British, French and German Media Discourses

The European Union (EU) has long sought to play a normative role in global energy governance, a role that requires a coherent, comprehensible and memorable image. Yet within its borders, there are divisions and discrepancies on energy, which may have an impact on the external reception of EU actions. France, Germany and the United Kingdom (UK), commonly referred to as ‘the EU’s big 3’, seem to have little in common on issues of energy policy. EU rhetoric on external energy matters places firm emphasis on three key ‘frames’ of understanding: sustainability, competitiveness and security of supply, yet the domestic rhetorics of France, Germany and the UK variously appear to place priority on one or more of these frames. This article explores media representations of the EU’s external energy relations from within the ‘Big 3’ EU member states and asks whether the EU’s normative agenda on external energy drives these media representations, or whether domestic member state interests dominate