Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice

Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice

Glycosphingolipids and neuroinflammation in parkinson''s disease

International audienceParkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson’s disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson’s disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson’s disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson’s disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson’s disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies

Les empreintes du temps : calendriers et rythmes sociaux

L’histoire du temps, telle qu’elle a été jusqu’alors construite par l’historiographie, a porté essentiellement sur l’expérience occidentale. Le regain récent des études sur le temps, lié au phénomène d’accélération et de déstructuration de celui-ci dans la modernité, a encore enrichi les savoirs, notamment sur la diversité des temps sociaux (temps du travail, du loisir, de la famille…). Or la place des espaces non-occidentaux dans ces réflexions demeure assez modeste. En outre, en ce qui concerne ces derniers, le temps est d’abord référé à la culture, et donc essentiellement à la dimension religieuse. Si celle-ci a une part importante dans la structuration du temps, notamment à travers l’élaboration des calendriers, le temps est aussi façonné par les multiples pratiques sociales imposées par les pouvoirs politiques et les autorités sociales et religieuses dominantes, ou initiées par les acteurs eux-mêmes. Les scansions calendaires et les cadres temporels nés des diverses activités induisent à leur tour des rythmes sociaux, à de multiples échelles, dont l’observation permet de saisir la façon dont ces temporalités sont choisies, appropriées, vécues par les individus et les groupes. Ce numéro propose quelques incursions dans l’espace arabe et musulman à partir de ces questionnements nouveaux sur et par le temps. Elles révèlent la façon dont s’est construite, sur la longue durée, une pluralité de références temporelles et calendaires dans cette région. Le temps ne peut en effet y être réduit à un seul « temps de l’islam », mais il s’inscrit dans un système complexe de circulation de modèles, d’emprunts, et aussi de conflits. Dans ce contexte, les acteurs ont appris à développer des compétences particulières pour passer d’un registre de temps à un autre