Schlegel lecteur de Lessing. Réflexions sur la construction d'un classique

International audienceLa confrontation de Schlegel avec Lessing inaugure une forme de critique littéraire particulièrement exigeante, qui ambitionne de comprendre "l'esprit" propre à l'oeuvre dans une étude attentive de sa forme. Conscient des problèmes interprétatifs que pose l'examen de textes quasiment contemporains, Schlegel accorde une large part de sa réflexion à la question du jugement critique, en particulier à travers le problème de la constitution d'un auteur en "classique". Appuyée dans son premier état sur une lecture fine des textes, l'interprétation de Schlegel tend à dégager par la suite des oeuvres un "esprit de Lessing", et cette appropriation aboutit à la récriture anthologique, puis à l'abstraction pure et simple, Lessing passant du côté de la philosophie. Mais même au cours de cette transformation, il demeure pour Schlegel l'occasion d'une réflexion poussée sur la forme de la philosophie (III, 97-102)

: Réflexions sur la construction d'un classique

International audienceLa confrontation de Schlegel avec Lessing inaugure une forme de critique littéraire particulièrement exigeante, qui ambitionne de comprendre "l'esprit" propre à l'oeuvre dans une étude attentive de sa forme. Conscient des problèmes interprétatifs que pose l'examen de textes quasiment contemporains, Schlegel accorde une large part de sa réflexion à la question du jugement critique, en particulier à travers le problème de la constitution d'un auteur en "classique". Appuyée dans son premier état sur une lecture fine des textes, l'interprétation de Schlegel tend à dégager par la suite des oeuvres un "esprit de Lessing", et cette appropriation aboutit à la récriture anthologique, puis à l'abstraction pure et simple, Lessing passant du côté de la philosophie. Mais même au cours de cette transformation, il demeure pour Schlegel l'occasion d'une réflexion poussée sur la forme de la philosophie (III, 97-102)

Neuronal retrograde transport of Borna disease virus occurs in signalling endosomes

International audienceLong-range axonal retrograde transport is a key mechanism for the cellular dissemination of neuroinvasive viruses, such as Borna disease virus (BDV), for which entry and egress sites are usually distant from the nucleus, where viral replication takes place. Although BDV is known to disseminate very efficiently in neurons, both in vivo and in primary cultures, the modalities of its axonal transport are still poorly characterized. In this work, we combined different methodological approaches, such as confocal microscopy and biochemical purification of endosomes, to study BDV retrograde transport. We demonstrate that BDV ribonucleoparticles (composed of the viral genomic RNA, nucleoprotein and phosphoprotein), as well as the matrix protein, are transported towards the nucleus into endocytic carriers. These specialized organelles, called signalling endosomes, are notably used for the retrograde transport of neurotrophins and activated growth factor receptors. Signalling endosomes have a neutral luminal pH and thereby offer protection against degradation during long-range transport. This particularity could allow the viral particles to be delivered intact to the cell body of neurons, avoiding their premature release in the cytoplasm

HSPA9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons

International audienceMortalin is a mitochondrial chaperone protein involved in quality control of proteins imported into the mitochondrial matrix, which was recently described as a sensor of neuronal stress. Mortalin is down-regulated in neurons of patients with neurodegenerative diseases and levels of Mortalin expression are correlated with neuronal fate in animal models of Alzheimer's disease or cerebral ischemia. To date, however, the links between Mortalin levels, its impact on mitochondrial function and morphology and, ultimately, the initiation of neurodegeneration, are still unclear. In the present study, we used lentiviral vectors to over- or under-express Mortalin in primary neuronal cultures. We first analyzed the early events of neurodegeneration in the axonal compartment, using oriented neuronal cultures grown in microfluidic-based devices. We observed that Mortalin down-regulation induced mitochondrial fragmentation and axonal damage, whereas its over-expression conferred protection against axonal degeneration mediated by rotenone exposure. We next demonstrated that Mortalin levels modulated mitochondrial morphology by acting on DRP1 phosphorylation, thereby further illustrating the crucial implication of mitochondrial dynamics on neuronal fate in degenerative diseases

A fourth isoform of endothelin-converting enzyme (ECE-1) is generated from an additional promoter molecular cloning and characterization

Human endothelin-converting enzyme (ECE-1) has been shown to exist as three isoforms (ECE-1a, ECE-1b and ECE-1c) diverging in their N-terminal sequence and displaying different patterns of subcellular localization. We report here the cloning of ECE-1d, a novel isoform of 767 amino acids, which is generated from the same gene via the existence of an additional promoter located upstream from the third exon of the ECE-1 gene. ECE-1d converting activity is comparable to that of the other three isoenzymes. In contrast to ECE-1b, ECE-1d is expressed at the cell surface, although less strongly than ECE-1a. We have also shown, by identifying ECE-1b and ECE-1d in rat, that the ECE-1 diversity is conserved between human and rodent, suggesting its physiological relevance. The mRNA levels of the four isoforms were assessed in the two species in various cell types, revealing some differences. In particular, the ECE-1a isoform, strongly expressed at the plasma membrane, was found to be highly expressed in primary cultures of endothelial cells but absent from primary cultures of smooth muscle cells

FerreAncillaryFaseb

Ancillary Data 1 to 4 of the Manuscript by Cécile A; Ferré et al

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease

International audienceMitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cell-permeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons

Data from: Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential

To favor their replication, viruses express proteins that target diverse mammalian cellular pathways. Due to the limited size of many viral genomes, such proteins are endowed with multiple functions, which require targeting to different subcellular compartments. One salient example is the X protein of Borna disease virus, which is expressed both at the mitochondria and in the nucleus. Moreover, we recently demonstrated that mitochondrial X protein is neuroprotective. In this study, we sought to examine the mechanisms whereby the X protein transits between subcellular compartments and to define its localization signals, to enhance its mitochondrial accumulation and thus, potentially, its neuroprotective activity. We transfected plasmids expressing fusion proteins bearing different domains of X fused to enhanced green fluorescent protein (eGFP) and compared their subcellular localization to that of eGFP. We observed that the 5–16 domain of X was responsible for both nuclear export and mitochondrial targeting and identified critical residues for mitochondrial localization. We next took advantage of these findings and constructed mutant X proteins that were targeted only to the mitochondria. Such mutants exhibited enhanced neuroprotective properties in compartmented cultures of neurons grown in microfluidic chambers, thereby confirming the parallel between mitochondrial accumulation of the X protein and its neuroprotective potential

Borna disease virus docks on neuronal DNA double-strand breaks to replicate and dampens neuronal activity

International audienceBorna disease viruses (BoDV) have recently emerged as zoonotic neurotropic pathogens. These persistent RNA viruses assemble nuclear replication centers (vSPOT) in close interaction with the host chromatin. However, the topology of this interaction and its consequences on neuronal function remain unexplored. In neurons, DNA double-strand breaks (DSB) have been identified as novel epigenetic mechanisms regulating neurotransmission and cognition. Activity-dependent DSB contribute critically to neuronal plasticity processes, which could be impaired upon infection. Here, we show that BoDV-1 infection, or the singled-out expression of viral Nucleoprotein and Phosphoprotein, increases neuronal DSB levels. Of interest, inducing DSB promoted the recruitment anew of vSPOT colocalized with DSB and increased viral RNA replication. BoDV-1 persistence decreased neuronal activity and response to stimulation by dampening the surface expression of glutamate receptors. Taken together, our results propose an original mechanistic cross talk between persistence of an RNA virus and neuronal function, through the control of DSB levels