Possible implication de glycosaminoglycanes dans la rétention du Grapevine fanleaf virus dans l’appareil alimentaire de son vecteur Xiphinema index

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New insights into Purkinje cell death mechanisms from organotypic cultures of prion protein-deficient cerebellum of Zch1 and Ngsk PrnP-/- transgenic mice

Current evidence clearly supports the promotion of neuronal survival as a main physiological function of the cellular prion protein PrPc, whereas the ectopic neuronal expression of its homologue Doppel (Dpl) leads to progressive cerebellar Purkinje cell death in prion protein-deficient Ngsk mice (NP0/0). Dpl neurotoxicity involves Bax-dependent apoptotic pathways, as well as other yet to be characterized cell death mechanisms in the NP0/0 Purkinje cells. Indeed, these neurons display increased amounts of several autophagy-related proteins such as the scrapie-responsive gene one (Scrg1), LC3B-II and p62, without any changes in their mRNA levels. In addition, autolysosomes accumulate in all neuronal compartments including axon terminals. These results suggest that Dpl toxicity impairs the autophagic flux, which may in turn trigger neuronal apoptosis, similar to that observed in other neurodegenerative conditions such as Alzheimer and prion diseases. In order to develop new therapies against neurodegenerative diseases, the interplay between multiple cell death pathways needs to be investigated in cellular and animal models of neurodegenerative diseases. For these reasons, we are examining autophagic events in the NP0/0 Purkinje cells rescued from neuronal death by Bax knock-out in the cerebellum of (Bax-/-; NP0/0) double mutant mice in order to determine if distinct mechanisms i.e. Bax-dependent apoptosis and autophagy, operate in these neurons. We are presently comparing the survival and development of Dpl-expressing, prion protein-deficient NP0/0 Purkinje cells with that of prion proteindeficient Zch1 Purkinje cells in cerebellar organotypic cultures. This study will enable us to distinguish specific toxic effects of prion protein deficiency from that of Dpl itself. Furthermore, the effects of autophagy-specific agents on Purkinje cell survival can be tested in this model.2 page(s

Are social inequalities in acute myeloid leukemia survival explained by differences in treatment utilization? Results from a French longitudinal observational study among older patients

International audienceBACKGROUND:Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization.METHODS:This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405).RESULTS:We found an influence of patients' socioeconomic position on survival (highest versus lowest position HRQ5: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HRQ5: 1.31[0.97;1.76] and cytogenetic prognosis HRQ5: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (ORQ5: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (ORQ5: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy.CONCLUSIONS:Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation

Prion protein (PrPc) immunocytochemistry and expression of the green fluorescent protein reporter gene under control of the bovine PrP gene promoter in the mouse brain.

Expression of the cellular prion protein (PrP(c)) by host cells is required for prion replication and neuroinvasion in transmissible spongiform encephalopathies. As a consequence, identification of the cell types expressing PrP(c) is necessary to determine the target cells involved in the cerebral propagation of prion diseases. To identify the cells expressing PrP(c) in the mouse brain, the immunocytochemical localization of PrP(c) was investigated at the cellular and ultrastructural levels in several brain regions. In addition, we analyzed the expression pattern of a green fluorescent protein reporter gene under the control of regulatory sequences of the bovine prion protein gene in the brain of transgenic mice. By using a preembedding immunogold technique, neuronal PrP(c) was observed mainly bound to the cell surface and presynaptic sites. Dictyosomes and recycling organelles in most of the major neuron types also exhibited PrP(c) antigen. In the olfactory bulb, neocortex, putamen, hippocampus, thalamus, and cerebellum, the distribution pattern of both green fluorescent protein and PrP(c) immunoreactivity suggested that the transgenic regulatory sequences of the bovine PrP gene were sufficient to promote expression of the reporter gene in neurons that express immunodetectable endogenous PrP(c). Transgenic mice expressing PrP-GFP may thus provide attractive murine models for analyzing the transcriptional activity of the Prnp gene during prion infections as well as the anatomopathological kinetics of prion diseases

Ataxia with Cerebellar Lesions in Mice Expressing Chimeric PrP-Dpl Protein.

International audienceMutations within the central region of prion protein (PrP) have been shown to be associated with severe neurotoxic activity similar to that observed with Dpl, a PrP-like protein. To further investigate this neurotoxic effect, we generated lines of transgenic (Tg) mice expressing three different chimeric PrP-Dpl proteins. Chi1 (amino acids 1-57 of Dpl replaced by amino acids 1-125 of PrP) and Chi2 (amino acids 1-66 of Dpl replaced by amino acids 1-134 of PrP) abrogated the pathogenicity of Dpl indicating that the presence of a N-terminal domain of PrP (23-134) reduced the toxicity of Dpl, as reported. However, when the amino acids 1-24 of Dpl were replaced by amino acids 1-124 of PrP, Chi3 Tg mice, which express the chimeric protein at a very low level, start developing ataxia at the age of 5-7 weeks. This phenotype was not counteracted by a single copy of full-length-PrP(c) but rather by its overexpression, indicating the strong toxicity of the chimeric protein Chi3. Chi3 Tg mice exhibit severe cerebellar atrophy with a significant loss of granule cells. We concluded that aa25 to aa57 of Dpl, which are not present in Chi1 and Chi2 constructs, confer toxicity to the protein. We tested this possibility by using the 25-57 Dpl peptide in primary culture of mouse embryo cortical neurons and found a significant neurotoxic effect. This finding identifies a protein domain that plays a role in mediating Dpl-related toxicity