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Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, we had previously found that Protein Misfolding Cyclic Amplification (PMCA) triggered the aggregation of aS, which is associated with a high resistance to the proteinase K (PK) digestion of both human and murine aS, a major hallmark of the disease-associated prion protein. In addition, PMCA was also able to trigger the aggregation of murine aS in C57Bl/6 mouse brains after seeding with sick M83 mouse brains. Here, we show that intracerebral inoculations of M83 mice with C57Bl/6-PMCA samples strikingly shortens the incubation period before the typical paralysis that develops in this transgenic model, demonstrating the pathogenicity of PMCA-aggregated murine aS. In the hind brain regions of these sick M83 mice containing lesions with an accumulation of aS phosphorylated at serine 129, aS also showed a high PK resistance in the N-terminal part of the protein. In contrast to M83 mice, old APPxM83 mice co-expressing human mutated amyloid precursor and presenilin 1 proteins were seen to have an aggregation of aS, especially in the cerebral cortex, hippocampus and striatum, which also contained the highest load of aS phosphorylated at serine 129. This was proven by three techniques: a Western blot analysis of PK-resistant aS; an ELISA detection of aS aggregates; or the identification of aggregates of aS using immunohistochemical analyses of cytoplasmic/neuritic aS deposits. The results obtained with the D37A6 antibody suggest a higher involvement of murine aS in APPxM83 mice than in M83 mice. Our study used novel tools for the molecular study of synucleinopathies, which highlight similarities with the molecular mechanisms involved in prion diseases.

Abstract The misfolded α-synuclein protein, phosphorylated at serine 129 (pSer129 α-syn), is the hallmark of Parkinson disease (PD). Detected also in the enteric nervous system (ENS), it supports the recent theory that PD could start in the gut, rather than the brain. In a previous study, using a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83), in which a neurodegenerative process associated with α-synuclein occurs spontaneously in the brain, we have shown earlier onset of pSer129 α-syn in the ENS. Here, we used this model to study the impact of paraquat (PQ) a neurotoxic herbicide incriminated in PD in agricultural workers) on the enteric pSer129 α-syn expression in young mice. Orally delivered in the drinking water at 10 mg/kg/day for 6–8 weeks, the impact of PQ was measured in a time-dependent manner on weight, locomotor abilities, pSer129 α-syn, and glial fibrillary acidic protein (GFAP) expression levels in the ENS. Remarkably, pSer129 α-syn was detected in ENS earlier under PQ oral exposure and enteric GFAP expression was also increased. These findings bring additional support to the theory that neurotoxic agents such as PQ initiate idiopathic PD after oral delivery.

Abstract The misfolded α-synuclein protein, phosphorylated at serine 129 (pSer129 α-syn), is the hallmark of Parkinson disease (PD). Detected also in the enteric nervous system (ENS), it supports the recent theory that PD could start in the gut, rather than the brain. In a previous study, using a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83), in which a neurodegenerative process associated with α-synuclein occurs spontaneously in the brain, we have shown earlier onset of pSer129 α-syn in the ENS. Here, we used this model to study the impact of paraquat (PQ) a neurotoxic herbicide incriminated in PD in agricultural workers) on the enteric pSer129 α-syn expression in young mice. Orally delivered in the drinking water at 10 mg/kg/day for 6-8 weeks, the impact of PQ was measured in a time-dependent manner on weight, locomotor abilities, pSer129 α-syn, and glial fibrillary acidic protein (GFAP) expression levels in the ENS. Remarkably, pSer129 α-syn was detected in ENS earlier under PQ oral exposure and enteric GFAP expression was also increased. These findings bring additional support to the theory that neurotoxic agents such as PQ initiate idiopathic PD after oral delivery.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of α-synuclein (α-syn) aggregates. The objective of this study was to investigate if β-synuclein (β-syn) overexpression could have beneficial effects by inhibiting the aggregation of α-syn. The M83 transgenic mouse is a model of synucleinopathy, which develops severe motor symptoms associated with aggregation of α-syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human β-syn gene (AAVβ-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. The M83 disease was - or not - accelerated using extracts of M83 brains injected with brain extract from mouse (M83) or human (MSA) origins. AAV vectors expression was confirmed using Western blot and ELISA technics. AAV mediated β-syn overexpression did not delay the disease onset or reduce the α-syn phosphorylated at serine 129 levels detected by ELISA, regardless of the AAV injection route and the inoculation of brain extracts. Instead, a proteinase-K resistant β-syn staining was detected by immunohistochemistry, specifically in sick M83 mice overexpressing β-syn after inoculation of AAVβ-syn. This study indicated for the first time that viral vector-mediated β-syn overexpression could form aggregates in a model of synucleinopathy.

On 18 July 1944, a convoy of German trucks was ambushed by the French Resistance near the village of Thorame-Haute in SE France. According to reports by French witnesses, the first German truck exploded. After a brief firefight, the Resistance pulled out without casualties, claiming that 58 Germans had been killed in the attack, including a high-ranking officer. The current project used witness interviews, archives materials, and metal detecting to validate the descriptions of the ambush. The project confirmed that at least nine German soldiers had been killed in the attack. The metal detecting survey recovered numerous small artefacts whose condition and dispersal indicated that a violent explosion had indeed occurred and had probably been preceded or followed by a fire. A grouping of fired cartridge casings was found in the former Resistance positions. The project was able to confirm the French accounts apart from the casualty figures.

Dans le cadre du projet de recherche BIOME (Bioindication Mares et Etangs) et du projet d'étude interdisciplinaire du Woerr, dix nouvelles localités de Tricholeiochiton fagesii ont été identifiées. Cette espèce n'avait à ce jour fait l'objet que de deux captures récentes en France dans la Brenne. Les résultats confirment la relative rareté de l'espèce, rencontrée dans moins de 5% des plans d'eau suivis, aux typologies variées.

Parkinson disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of alpha-synuclein (a-syn) aggregates. The objective of this study was to investigate if beta-synuclein (b-syn) overexpression could have beneficial effects by inhibiting the aggregation of a-syn. The M83 transgenic mouse is a model of synucleinopathy, which develops severe motor symptoms associated with aggregation of a-syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human b-syn gene (AAVb-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. One or two months later, M83 disease was accelerated or not using brain M83 extracts from mouse (M83) or human (MSA) origins. AAV mediated b-syn overexpression detected by ELISA did not delay the disease onset, regardless of the AAV injection route and of the inoculation of brain extracts. Accordingly, phosphorylated a-syn levels detected by ELISA in sick mice were similar after injecting AAVb-syn or AAVGFP. Instead, immunohistochemistry analysis of b-syn indicated the presence of proteinase-K resistant b-syn staining specifically in sick M83 mice inoculated with AAVb-syn. This study indicated for the first time that b-syn could form aggregates in a model of synucleinopathy when it is expressed by a viral vector.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of α-synuclein (α-syn) aggregates. The objective of this study was to investigate if β-synuclein (β-syn) overexpression could have beneficial effects by inhibiting the aggregation of α-syn. The M83 transgenic mouse is a model of synucleinopathy, which develops severe motor symptoms associated with aggregation of α-syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human β-syn gene (AAVβ-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. One or two months later, M83 disease was accelerated or not using brain M83 extracts from mouse (M83) or human (MSA) origins. AAV mediated β-syn overexpression detected by ELISA did not delay the disease onset, regardless of the AAV injection route and of the inoculation of brain extracts. Accordingly, phosphorylated α-syn levels detected by ELISA in sick mice were similar after injecting AAVβ-syn or AAVGFP. Instead, immunohistochemistry analysis of β-syn indicated the presence of proteinase-K resistant β-syn staining specifically in sick M83 mice inoculated with AAVβ-syn. This study indicated for the first time that β-syn could form aggregates in a model of synucleinopathy when it is expressed by a viral vector.

Although Escherichia coli Nissle 1917 (EcN) has been used therapeutically for over a century, the determinants of its probiotic properties remain elusive. EcN produces two siderophore-microcins (Mcc) responsible for an antagonistic activity against other Enterobacteriaceae. EcN also synthesizes the genotoxin colibactin encoded by the pks island. Colibactin is a virulence factor and a putative pro-carcinogenic compound. Therefore, we aimed to decouple the antagonistic activity of EcN from its genotoxic activity. We demonstrated that the pks-encoded ClbP, the peptidase that activates colibactin, is required for the antagonistic activity of EcN. The analysis of a series of ClbP mutants revealed that this activity is linked to the transmembrane helices of ClbP and not the periplasmic peptidase domain, indicating the transmembrane domain is involved in some aspect of Mcc biosynthesis or secretion. A single amino acid substitution in ClbP inactivates the genotoxic activity but maintains the antagonistic activity. In an in vivo salmonellosis model, this point mutant reduced the clinical signs and the fecal shedding of Salmonella similarly to the wild type strain, whereas the clbP deletion mutant could neither protect nor outcompete the pathogen. The ClbP-dependent antibacterial effect was also observed in vitro with other E. coli strains that carry both a truncated form of the Mcc gene cluster and the pks island. In such strains, siderophore-Mcc synthesis also required the glucosyltransferase IroB involved in salmochelin production. This interplay between colibactin, salmochelin, and siderophore-Mcc biosynthetic pathways suggests that these genomic islands were co-selected and played a role in the evolution of E. coli from phylogroup B2. This co-evolution observed in EcN illustrates the fine margin between pathogenicity and probiotic activity, and the need to address both the effectiveness and safety of probiotics. Decoupling the antagonistic from the genotoxic activity by specifically inactivating ClbP peptidase domain opens the way to the safe use of EcN.

It is well known that women live longer than men. This gap is observed in most human populations and can even reach 10–15 years. In addition, most of the known super centenarians (i.e., humans who lived for > 110 years) are women. The differences in life expectancy between men and women are often attributed to cultural differences in common thinking. However, sex hormones seem to influence differences in the prevalence of diseases, in the magnitude of aging, and in the longevity between men and women. Moreover, far from being human specific, the sex gap in longevity is extremely common in non-human animals, especially in mammals. Biological factors clearly contribute to such a sex gap in aging and longevity. Different hypotheses have been proposed to explain why males and females age and die differently. The cost of sexual selection and sexual dimorphism has long been considered the best explanation for the observed sex gap in aging/longevity. However, the way mitochondria are transmitted (i.e., through females in most species) could have an effect, called the mother’s curse. Recent data suggest that sex chromosomes may also contribute to the sex gap in aging/longevity through several potential mechanisms, including the unguarded X/Z, the toxic Y/W and the loss of Y/W. We discuss future research directions to test these ideas.