Two-Dimensional Electrophoresis of Tau Mutants Reveals Specific Phosphorylation Pattern Likely Linked to Early Tau Conformational Changes

The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, “human neuronal cell lines” overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation

Des acteurs clés de la régulation de la sécrétion de GnRH : les cellules gliales et endothéliales de l’hypothalamus

De nombreux travaux publiés ces dix dernières années démontrent que la sécrétion de GnRH est susceptible d’être modulée par des facteurs provenant de cellules gliales mais aussi de l’endothélium des capillaires du plexus porte. Parmi les facteurs gliaux susceptibles d’intervenir, on peut distinguer le TGFβ qui peut agir directement sur les cellules à GnRH et les EGFs qui exercent leurs actions clairement stimulantes via la sécrétion de prostaglandine par les cellules astrocytaires voisines. Pour l’endothélium, il a été montré qu’il pouvait favoriser la libération de GnRH via la sécrétion de NO. En parallèle à ces actions, la glie et l’endothélium sont capables de moduler la sécrétion de GnRH en favorisant l’accès des terminaisons nerveuses à l’espace péricapillaire afin de faciliter le déversement de la neurohormone dans le sang porte. De fait, les terminaisons ne sont en situation de pouvoir déverser leur contenu que l’après midi du prooestrus, période où un pic de GnRH est nécessaire afin de provoquer le pic préovulatoire de LH. Cette observation suggère qu’il existe une plasticité morphologique de l’éminence médiane mettant en cause des mouvements des tanycytes (épendymocytes de l’éminence médiane). Cette plasticité peut être induite par des facteurs de croissances gliaux (TGFβ et TGFα) et par le NO d’origine endothéliale. Au site de libération de la GnRH, l’interaction neuro-glio-endothéliale apparaît donc un élément clé de la régulation de sécrétion de GnRH

Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity

International audienceA neuropeptide was isolated from a frog brain extract by HPLC purification and characterized by mass spectrometry. This 26-aa neuropeptide, which belongs to the RFamide peptide family, was designated 26RFa, and its primary structure was established as VGTALGSLAEELNGYNRKKGGFSFRF-NH2. Research in databases revealed the presence of sequences homologous to frog 26RFa in the human genome and in rat ESTs. On the basis of this sequence information, the cDNAs encoding the human and rat 26RFa precursors were cloned. The two preproteins show a similar organization, with the 26RFa sequence located in the C-terminal region of the precursor. Human preprotein (prepro)-26RFa encodes an additional putative RFamide peptide that is not found in the rat precursor. The primary structures of human, rat, and frog 26RFa exhibit approximately 80% identity, and the C-terminal octapeptide has been fully conserved from amphibians to mammals. In situ hybridization histochemistry revealed that, in the rat brain, the 26RFa gene is exclusively expressed in the ventromedial hypothalamic nucleus and in the lateral hypothalamic area. 26RFa induced a dose-dependent stimulation in cAMP production by rat pituitary cells in vitro and markedly increased food intake in mice. The conservation of the primary structure of 26RFa during vertebrate evolution, the discrete localization of the mRNA encoding its precursor in hypothalamic nuclei involved in the control of feeding behavior, and the observation that 26RFa possesses orexigenic properties indicate that this neuropeptide may play important biological functions

Structure and functions of the novel hypothalamic RFamide neuropeptides R-RFa and 26RFa in vertebrates

International audienceA number of RFamide peptides have been characterized in invertebrate species and these peptides have been found to exert a broad spectrum of biological activities. In contrast, in vertebrates, our knowledge on RFamide peptides is far more limited and only a few members of the RFamide peptide family have been identified in various vertebrate classes during the last years. The present review focuses on two novel RFamide peptides, Rana RFamide (R-RFa) and 26RFa, that have been recently isolated from the amphibian brain. R-RFa shares the C-terminal LPLRFamide motif with other RFamide peptides previously identified in mammals, birds and fish. The distribution of R-RFa in the frog brain exhibits strong similarities with those of other LPLRFamide peptides, notably in the periventricular region of the hypothalamus. There is also evidence that the physiological functions of R-RFa and other LPLRFamide peptides have been conserved from fish to mammals; in particular, all these peptides appear to be involved in the control of pituitary hormone secretion. 26RFa does not exhibit any significant structural identity with other RFamide peptides and this peptide is the only member of the family that possesses an FRFamide motif at its C-terminus. The strong conservation of the primary structure of 26RFa from amphibians to mammals suggests that this RFamide peptide is involved in important biological functions in vertebrates. As for several other RFamide peptides, 26RFa-containing neurons are present in the hypothalamus, notably in two nuclei involved in the control of feeding behavior. Indeed, 26RFa is a potent stimulator of appetite in mammals. Concurrently, recent data suggest that 26RFa exerts various neuroendocrine regulatory activities at the pituitary and adrenal level

Biochemical characterization and immunohistochemical localization of urotensin II in the human brainstem and spinal cord

International audienceThe human urotensin II (UII) precursor encompasses several potential cleavage sites and thus, processing of pro-UII may generate various forms of mature UII including the peptides of 11 (UII11), 16 (UII16) and 19 (UII19) residues. Until now, the native form of human UII had not been characterized. Here, we show that the major UII peptide occurring in the human spinal cord corresponds to UII11. In contrast, neither the UII16 nor the UII19 forms could be detected. In 50% of the brainstem and in all the spinal cord extracts analysed, a second minor UII-immunoreactive peptide was resolved. Immunohistochemical labelling of the cervical segment of the human spinal cord revealed that the UII-immunoreactive material was confined to a subset of ventral horn motoneurones. These data provide the first evidence that in the human, the UII precursor, expressed in motoneurones, is processed at the tribasic KKR93 cleavage site to generate a mature form of UII of 11 amino acids. The absence of N-terminally elongated forms of UII of 16 and 19 residues indicates that pro-UII is not cleaved at the R85 or K88 monobasic sites. Finally, the minor UII-immunoreactive peptide detected in several tissue extracts might correspond to an extended form of UII resulting from the processing of the UII precursor at the basic RK50 or RK66 doublets

Réseaux et mobilité

1.1. Les supports matériels des réseaux et de la mobilité (Pierre Beauvillain, Pierre Chavel, Claude Chappert, Didier Decoster, Line Garnero, Antonio Munoz-Yague, Raymond Quéré, Paul-Alain Rolland, Joseph Saillard, Jean Pierre Sanchez) 1.1.1. Introduction En deçà des architectures de réseaux, la mise au point de leurs composants, de leurs circuits et de leurs systèmes, constitue l’une des clés du succès. Ces recherches sont guidées par les exigences de débit, d’adaptabilité, de fiabilité et d..