Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2 R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2 R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2 R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.National Institutes of Health (U.S.) (Grant NS78839

On the promise of glycogen phosphorylase inhibition in acute inflammation

How glycogen metabolism directly regulates macrophages in the acute inflammatory state is not well understood. In the recent issue of Nature Communications, Ma et al. provide new insight into this process, demonstrating that glycogenolysis-driven pentose phosphate pathway and UDP-glucose-driven P2Y14 receptor promote an inflammatory phenotype in macrophages. They show that in vivo blockade of glycogenolysis is sufficient to rescue survival in peritonitis, hepatitis, and sepsis. Their results hold implications for the treatment of acute inflammatory disorders at large. </jats:p

FSMP-17. GLOBAL METABOLOMIC PROFILING OF GLIOBLASTOMA MULTIFORME REVEALS METABOLIC VULNERABILITIES IN RESPONSE TO RADIATION THERAPY

Abstract Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, originates in astrocytes and oligodendrocytes and yields a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat the poor prognosis of GBM. Recent studies have established that GBM cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived GBM cell lines. Surprisingly, acute high dosage of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), a non-proteinogenic amino acid. Fractionation of radiation therapy resulted in dose-dependent changes in the heme synthesis pathway within these cells. Using an orthotopic xenograft mouse model of GBM, we identify several enzymatic vulnerabilities in vivo and discuss a novel combinatorial therapeutic approach of radiation and targeted pharmacological intervention. Our findings reveal the fundamental biosynthetic changes that GBMs adopt when exposed to ionizing irradiation as well as the benefits of a combinatorial approach.</jats:p

Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy

Abstract Background Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis. Methods We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction. Results LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment. Conclusions LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy. </jats:sec