Altération métabolique et déficit synaptique dans la maladie d'Alzheimer : rôle de la PHGDH astrocytaire

An early alteration of both cerebral glucose metabolism and synaptic activity has been consistently described in Alzheimer's disease (AD) patients. Metabolism of glucose via glycolysis and the citric acid cycle produces ATP that is essential for synaptic activity and plasticity. In the brain, glucose is predominantly processed glycolytically into astrocytes and not by neurons. Beyond ATP production, a major function of aerobic glycolysis is to provide precursors to support macromolecular synthesis. L-serine, generated from glucose through diversion of the glycolytic intermediate 3-phosphoglycerate (3PG) into the phosphorylated pathway, is only produced in astrocytes by 3-phosphoglycerate dehydrogenase (PHGDH), selectively expressed in those glial cells. L-serine is the precursor of D-serine, the main co-agonist of synaptic NMDAR, required for synaptic activity and plasticity. We used 3xTg-AD mice, which develop a progressive pathology, to investigate whether a defective production of L-/D-serine contributes to early synaptic deficits in AD. We found that 3xTg-AD mice display early in vivo alterations of glucose metabolism, synaptic deficits (LTP) in the CA1 region and also lower concentration of L-serine. The local expression of PHGDH was significantly altered. Exogenous D-serine completely rescued LTP in 3xTg-AD mice. These data support the hypothesis that a deficit of L-serine synthesis by astrocytes likely mediated by a decreased glycolytic flux may be responsible for the synaptic alteration mediated by NMDAR in the hippocampus of 3xTg-AD mice.Les patients atteints de la MA souffrent d'altérations métaboliques et synaptiques précoces. Via la glycolyse et le cycle de Krebs, le métabolisme du glucose permet la production d'ATP, essentielle à l'activité et la plasticité synaptique. Contrairement aux neurones, les astrocytes utilisent majoritairement la glycolyse pour métaboliser le glucose. En plus de la production d'énergie, la glycolyse fournit les précurseurs indispensables à la synthèse de biomolécules comme la L-sérine. Cet acide aminé est produit à partir du glucose par la déviation du 3-phosphoglycérate (3PG), un intermédiaire glycolytique, via l'enzyme 3-phosphoglycérate déshydrogénase (PHGDH), exprimée spécifiquement dans les astrocytes. La L-sérine est le précurseur de la D-sérine, le principal co-agoniste des NMDAR nécessaires à l'activité et la plasticité synaptique.Nous avons utilisé des souris 3xTg-AD, un modèle développant une MA progressive, afin d'étudier si une altération de la production de L-/D-sérine pouvait contribuer à des déficits synaptiques.A 6 mois, lorsque les souris 3xTg-AD ne possèdent pas encore de plaques amyloïdes dans l'hippocampe, nous avons observé in vivo une diminution du métabolisme du glucose, de la concentration de L-sérine et des déficits synaptiques (LTP). L'expression locale de la PHGDH est aussi altérée. L'application de D-sérine restaure complètement les déficits de LTP chez les souris 3xTg-AD.Ces données supportent l'hypothèse qu'un déficit de production de L-sérine par les astrocytes médié par une diminution du flux glycolytique serait responsable de l'altération synaptique observée dans l'hippocampe des souris 3xTg-AD

Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage

The introduction of the highly active antiretroviral therapy (HAART) has greatly improved survival. However, these treatments fail to definitively cure the patients and unveil the presence of quiescent HIV-1 reservoirs like cells from monocyte-macrophage lineage. A purge, or at least a significant reduction of these long lived HIV-1 reservoirs will be needed to raise the hope of the viral eradication. This review focuses on the molecular mechanisms responsible for viral persistence in cells of the monocyte-macrophage lineage. Controversy on latency and/or cryptic chronic replication will be specifically evoked. In addition, since HIV-1 infected monocyte-macrophage cells appear to be more resistant to apoptosis, this obstacle to the viral eradication will be discussed. Understanding the intimate mechanisms of HIV-1 persistence is a prerequisite to devise new and original therapies aiming to achieve viral eradication

CTIP2, une protéine multifonctionnelle : Implication en physiopathologie cellulaire et en thérapeutique

The transcription factor CTIP2 (BCL11B) is a multifunctional protein involved in numerous cell physiological processes. To date, many molecular mechanisms underlying this process have been discovered, which highlighted the importance of the epigenetic regulation of genes and the regulation of the elongation factor P-TEFb. Furthermore studies of the deregulation of CTIP2 showed the association of CTIP2 to numerous pathologies including cancer and cardiac hypertrophy. A better comprehension of the physiopathology of these diseases might lead to the design of therapeutical strategies intending to prevent CTIP2 deregulation. Moreover, CTIP2 and its associated proteins constitute potential targets in strategies aiming to reduce and/or purge HIV-1 cell reservoirs. English title : CTIP2, a multifunctional protein: cellular physiopathology and therapeutic implication

LSD1 cooperates with CTIP2 to promote HIV-1 transcriptional silencing

Microglial cells are the main HIV-1 targets in the central nervous system (CNS) and constitute an important reservoir of latently infected cells. Establishment and persistence of these reservoirs rely on the chromatin structure of the integrated proviruses. We have previously demonstrated that the cellular cofactor CTIP2 forces heterochromatin formation and HIV-1 gene silencing by recruiting HDAC and HMT activities at the integrated viral promoter. In the present work, we report that the histone demethylase LSD1 represses HIV-1 transcription and viral expression in a synergistic manner with CTIP2. We show that recruitment of LSD1 at the HIV-1 proximal promoter is associated with both H3K4me3 and H3K9me3 epigenetic marks. Finally, our data suggest that LSD1-induced H3K4 trimethylation is linked to hSET1 recruitment at the integrated provirus

Human-Phosphate-Binding-Protein inhibits HIV-1 gene transcription and replication

The Human Phosphate-Binding protein (HPBP) is a serendipitously discovered lipoprotein that binds phosphate with high affinity. HPBP belongs to the DING protein family, involved in various biological processes like cell cycle regulation. We report that HPBP inhibits HIV-1 gene transcription and replication in T cell line, primary peripherical blood lymphocytes and primary macrophages. We show that HPBP is efficient in naïve and HIV-1 AZT-resistant strains. Our results revealed HPBP as a new and potent anti HIV molecule that inhibits transcription of the virus, which has not yet been targeted by HAART and therefore opens new strategies in the treatment of HIV infection

Knockout studies reveal an important role of <i>plasmodium</i> lipoic acid protein ligase a1 for asexual blood stage parasite survival

Lipoic acid (LA) is a dithiol-containing cofactor that is essential for the function of a-keto acid dehydrogenase complexes. LA acts as a reversible acyl group acceptor and 'swinging arm' during acyl-coenzyme A formation. The cofactor is post-translationally attached to the acyl-transferase subunits of the multienzyme complexes through the action of octanoyl (lipoyl): &lt;i&gt;N&lt;/i&gt;-octanoyl (lipoyl) transferase (LipB) or lipoic acid protein ligases (LplA). Remarkably, apicomplexan parasites possess LA biosynthesis as well as scavenging pathways and the two pathways are distributed between mitochondrion and a vestigial organelle, the apicoplast. The apicoplast-specific LipB is dispensable for parasite growth due to functional redundancy of the parasite's lipoic acid/octanoic acid ligases/transferases. In this study, we show that &lt;i&gt;LplA1&lt;/i&gt; plays a pivotal role during the development of the erythrocytic stages of the malaria parasite. Gene disruptions in the human malaria parasite &lt;i&gt;P.falciparum&lt;/i&gt; consistently were unsuccessful while in the rodent malaria model parasite &lt;i&gt;P. berghei&lt;/i&gt; the &lt;i&gt;LplA1&lt;/i&gt; gene locus was targeted by knock-in and knockout constructs. However, the &lt;i&gt;LplA1&lt;/i&gt; &lt;sup&gt;(-)&lt;/sup&gt; mutant could not be cloned suggesting a critical role of LplA1 for asexual parasite growth &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. These experimental genetics data suggest that lipoylation during expansion in red blood cells largely occurs through salvage from the host erythrocytes and subsequent ligation of LA to the target proteins of the malaria parasite

Effect of fluorine on near-liquidus phase equilibria of an Fe–Mg rich basalt

Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Chemical Geology 312-313 (2012): 118-126, doi:10.1016/j.chemgeo.2012.04.015.Volatile species (H2O, CO2, F, Cl, etc) have important effects on the formation and crystallization history of basaltic magmas. Here, we have experimentally investigated the effects of F on phase equilibria of Fe-Mg-rich basalt. Our results show that fluorine has large effects on the liquidus temperature and the chemistry of crystallizing minerals. Compared to the F-free system, addition of ~2 wt.% F moves the olivine-pigeonite liquidus point down ~2 kbar and 95 °C (from 12 kbar, 1375 °C to 10 kbar, 1280 °C). With increasing fluorine concentrations, dramatically increases for both pyroxene and olivine, suggesting that fluorine in basaltic magmas complexes primarily with MgO. Complexing with MgO in the melt decreases its MgO activity, and forces the crystallizing minerals to greater Fe/Mg, and so increases . Models of basalt generation, where the magma is fluorine-rich, need to include the effect of not only water but fluorine on liquidus depression and minerals crystallizing/melting. Our results suggest that fluorine may significantly aid in the petrogenesis of silica-poor, alkali-rich magmas in the Earth and Mars.This work was supported by NASA MFR grant # NNX09AL25G to A.H. Treiman and J. Filiberto, a Lunar and Planetary Institute summer internship to J. Wood, and a Packard fellowship for science and engineering to R. Dasgupta

Pliocene-Quaternary crustal melting in central and northern Tibet and insights into crustal flow

There is considerable controversy over the nature of geophysically recognized low-velocity-high-conductivity zones (LV-HCZs) within the Tibetan crust, and their role in models for the development of the Tibetan Plateau. Here we report petrological and geochemical data on magmas erupted 4.7-0.3 Myr ago in central and northern Tibet, demonstrating that they were generated by partial melting of crustal rocks at temperatures of 700-1,050°C and pressures of 0.5-1.5 GPa. Thus Pliocene-Quaternary melting of crustal rocks occurred at depths of 15-50 km in areas where the LV-HCZs have been recognized. This provides new petrological evidence that the LV-HCZs are sources of partial melt. It is inferred that crustal melting played a key role in triggering crustal weakening and outward crustal flow in the expansion of the Tibetan Plateau

Achieving a cure for HIV infection: do we have reasons to be optimistic?

The introduction of highly active antiretroviral therapy (HAART) in 1996 has transformed a lethal disease to a chronic pathology with a dramatic decrease in mortality and morbidity of AIDS-related symptoms in infected patients. However, HAART has not allowed the cure of HIV infection, the main obstacle to HIV eradication being the existence of quiescent reservoirs. Several other problems have been encountered with HAART (such as side effects, adherence to medication, emergence of resistance and cost of treatment), and these motivate the search for new ways to treat these patients. Recent advances hold promise for the ultimate cure of HIV infection, which is the topic of this review. Besides these new strategies aiming to eliminate the virus, efforts must be made to improve current HAART. We believe that the cure of HIV infection will not be attained in the short term and that a strategy based on purging the reservoirs has to be associated with an aggressive HAART strategy