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1.
Biophys J ; 123(11): 1508-1518, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38664966

RESUMEN

Biomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly in the nucleus where phase separation is thought to underly elements of chromatin organization and regulation. Specifically, it has been recently reported that phase separation of heterochromatin protein 1alpha (HP1α) with DNA contributes to the formation of condensed chromatin states. HP1α localization to heterochromatic regions is mediated by its binding to specific repressive marks on the tail of histone H3, such as trimethylated lysine 9 on histone H3 (H3K9me3). However, whether epigenetic marks play an active role in modulating the material properties of HP1α and dictating emergent functions of its condensates remains to be understood. Here, we leverage a reductionist system, composed of modified and unmodified histone H3 peptides, HP1α, and DNA, to examine the contribution of specific epigenetic marks to phase behavior of HP1α. We show that the presence of histone peptides bearing the repressive H3K9me3 is compatible with HP1α condensates, whereas peptides containing unmodified residues or bearing the transcriptional activation mark H3K4me3 are incompatible with HP1α phase separation. Using fluorescence microscopy and rheological approaches, we further demonstrate that H3K9me3 histone peptides modulate the dynamics and viscoelastic network properties of HP1α condensates in a concentration-dependent manner. Additionally, in cells exposed to uniaxial strain, we find there to be a decreased ratio of nuclear H3K9me3 to HP1α. These data suggest that HP1α-DNA condensates are viscoelastic materials, whose properties may provide an explanation for the dynamic behavior of heterochromatin in cells and in response to mechanostimulation.


Asunto(s)
Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona , Epigénesis Genética , Histonas , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/química , Histonas/metabolismo , Histonas/química , Humanos , ADN/metabolismo , ADN/química , Condensados Biomoleculares/metabolismo , Condensados Biomoleculares/química
2.
Glia ; 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39344832

RESUMEN

The molecules that constitute myelin are critical for the integrity of axon/myelin-units and thus speed and precision of impulse propagation. In the CNS, the protein composition of oligodendrocyte-derived myelin has evolutionarily diverged and differs from that in the PNS. Here, we hypothesized that the CNS myelin proteome also displays variations within the same species. We thus used quantitative mass spectrometry to compare myelin purified from mouse brains at three developmental timepoints, from brains of male and female mice, and from four CNS regions. We find that most structural myelin proteins are of approximately similar abundance across all tested conditions. However, the abundance of multiple other proteins differs markedly over time, implying that the myelin proteome matures between P18 and P75 and then remains relatively constant until at least 6 months of age. Myelin maturation involves a decrease of cytoskeleton-associated proteins involved in sheath growth and wrapping, along with an increase of all subunits of the septin filament that stabilizes mature myelin, and of multiple other proteins which potentially exert protective functions. Among the latter, quinoid dihydropteridine reductase (QDPR) emerges as a highly specific marker for mature oligodendrocytes and myelin. Conversely, female and male mice display essentially similar myelin proteomes. Across the four CNS regions analyzed, we note that spinal cord myelin exhibits a comparatively high abundance of HCN2-channels, required for particularly long sheaths. These findings show that CNS myelination involves developmental maturation of myelin protein composition, and regional differences, but absence of evidence for sexual dimorphism.

3.
Semin Cell Dev Biol ; 116: 38-44, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33092959

RESUMEN

The past decade has seen an important revision of the traditional concept of the role and function of glial cells. From "passive support" for neurons, oligodendrocyte lineage cells are now recognized as metabolic exchangers with neurons, a cellular interface with blood vessels and responders to gut-derived metabolites or changes in the social environment. In the developing brain, the differentiation of neonatal oligodendrocyte progenitors (nOPCs) is required for normal brain function. In adulthood, the differentiation of adult OPCs (aOPCs) serves an important role in learning, behavioral adaptation and response to myelin injury. Here, we propose the concept of OPCs as environmental biosensors, which "sense" chemical and physical stimuli over time and adjust to the new challenges by modifying their epigenome and consequent transcriptome. Because epigenetics defines the ability of the cell to "adapt" gene expression to changes in the environment, we propose a model of OPC differentiation resulting from time-dependent changes of the epigenomic landscape in response to declining mitogens, raising hormone levels, neuronal activity, changes in space constraints or stiffness of the extracellular matrix. We propose that the intrinsically different functional properties of aOPCs compared to nOPCs result from the accrual of "epigenetic memories" of distinct events, which are "recorded" in the nuclei of OPCs as histone and DNA marks, defining a "unique epigenomic landscape" over time.


Asunto(s)
Técnicas Biosensibles/métodos , Epigénesis Genética/genética , Oligodendroglía/metabolismo , Células Madre/metabolismo , Humanos
4.
Brain ; 145(2): 569-583, 2022 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-34894211

RESUMEN

The identification of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication, and yet the question regarding the identity of the components responsible for this cross-talk remains open. We previously reported that relapsing remitting multiple sclerosis patients treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and CSF samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identified the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate-treated relapsing remitting multiple sclerosis patients. The levels of the identified metabolites of bacterial origin (p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neurofilament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Animales , Biomarcadores , Dimetilfumarato/uso terapéutico , Humanos , Indicán , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Fenol , Ratas
5.
Glia ; 70(2): 321-336, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34687571

RESUMEN

The N-myc downstream regulated gene family member 1 (NDRG1) is a gene whose mutation results in peripheral neuropathy with central manifestations. While most of previous studies characterized NDRG1 role in Schwann cells, the detection of central nervous system symptoms and the identification of NDRG1 as a gene silenced in the white matter of multiple sclerosis brains raise the question regarding its role in oligodendrocytes. Here, we show that NDRG1 is enriched in oligodendrocytes and myelin preparations, and we characterize its expression using a novel reporter mouse (TgNdrg1-EGFP). We report NDRG1 expression during developmental myelination and during remyelination after cuprizone-induced demyelination of the adult corpus callosum. The transcriptome of Ndrg1-EGFP+ cells further supports the identification of late myelinating oligodendrocytes, characterized by expression of genes regulating lipid metabolism and bioenergetics. We also generate a lineage specific conditional knockout (Olig1cre/+ ;Ndrg1fl/fl ) line to study its function. Null mice develop normally, and despite similar numbers of progenitor cells as wild type, they have fewer mature oligodendrocytes and lower levels of myelin proteins than controls, thereby suggesting NDRG1 as important for the maintenance of late myelinating oligodendrocytes. In addition, when control and Ndrg1 null mice are subject to cuprizone-induced demyelination, we observe a higher degree of demyelination in the mutants. Together these data identify NDRG1 as an important molecule for adult myelinating oligodendrocytes, whose decreased levels in the normal appearing white matter of human MS brains may result in greater susceptibility of myelin to damage.


Asunto(s)
Esclerosis Múltiple , Vaina de Mielina , Animales , Cuprizona/toxicidad , Familia , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo
6.
Neurochem Res ; 45(3): 606-619, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32020491

RESUMEN

Differentiation of oligodendrocytes (OL) from progenitor cells (OPC) is the result of a unique program of gene expression, which is further regulated by the formation of topological domains of association with the nuclear lamina. In this study, we show that cultured OPC were characterized by progressively declining levels of endogenous Lamin B1 (LMNB1) during differentiation into OL. We then identify the genes dynamically associated to the nuclear lamina component LMNB1 during this transition, using a well established technique called DamID, which is based on the ability of a bacterially-derived deoxyadenosine methylase (Dam), to modify genomic regions in close proximity. We expressed a fusion protein containing Dam and LMNB1 in OPC (OPCLMNB1-Dam) and either kept them proliferating or differentiated them into OL (OLLMNB1-Dam) and identified genes that were dynamically associated to LMNB1 with differentiation. Importantly, we identified Lss, the gene encoding for lanosterol synthase, a key enzyme in cholesterol synthesis, as associated to the nuclear lamina in OLLMNB1-Dam. This finding could at least in part explain the lipid dysregulation previously reported for mouse models of ADLD characterized by persistent LMNB1 expression in oligodendrocytes.


Asunto(s)
Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Células Precursoras de Oligodendrocitos/fisiología , Animales , Diferenciación Celular/fisiología , Núcleo Celular/genética , Núcleo Celular/metabolismo , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Lámina Nuclear/genética , Lámina Nuclear/metabolismo , Células Precursoras de Oligodendrocitos/citología , Células Precursoras de Oligodendrocitos/metabolismo
7.
Brain ; 142(3): 647-661, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30698680

RESUMEN

Cell-permeable formulations of metabolites, such as fumaric acid esters, have been used as highly effective immunomodulators in patients with multiple sclerosis and yet their mechanism of action remains elusive. Since fumaric acid esters are metabolites, and cell metabolism is highly intertwined with the epigenetic regulation of gene expression, we investigated whether this metabolic-epigenetic interplay could be leveraged for therapeutic purposes. To this end we recruited 47 treatment-naïve and 35 fumaric acid ester-treated patients with multiple sclerosis, as well as 16 glatiramer acetate-treated patients as a non-metabolite treatment control. Here we identify a significant immunomodulatory effect of fumaric acid esters on the expression of the brain-homing chemokine receptor CCR6 in CD4 and CD8 T cells of patients with multiple sclerosis, which include T helper-17 and T cytotoxic-17 cells. We report differences in DNA methylation of CD4 T cells isolated from untreated and treated patients with multiple sclerosis, using the Illumina EPIC 850K BeadChip. We first demonstrate that Krebs cycle intermediates, such as fumaric acid esters, have a significantly higher impact on epigenome-wide DNA methylation changes in CD4 T cells compared to amino-acid polymers such as glatiramer acetate. We then define a fumaric acid ester treatment-specific hypermethylation effect on microRNA MIR-21, which is critical for the differentiation of T helper-17 cells. This hypermethylation effect was attributed to the subpopulation of T helper-17 cells using a decomposition analysis and was further validated in an independent prospective cohort of seven patients before and after treatment with fumaric acid esters. In vitro treatment of CD4 and CD8 T cells with fumaric acid esters supported a direct and dose-dependent effect on DNA methylation at the MIR-21 promoter. Finally, the upregulation of miR-21 transcripts and CCR6 expression was inhibited if CD4 or CD8 T cells stimulated under T helper-17 or T cytotoxic-17 polarizing conditions were treated with fumaric acid esters in vitro. These data collectively define a direct link between fumaric acid ester treatment and hypermethylation of the MIR-21 locus in both CD4 and CD8 T cells and suggest that the immunomodulatory effect of fumaric acid esters in multiple sclerosis is at least in part due to the epigenetic regulation of the brain-homing CCR6+ CD4 and CD8 T cells.


Asunto(s)
Fumaratos/metabolismo , Esclerosis Múltiple/metabolismo , Adulto , Encéfalo/inmunología , Encéfalo/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Fumaratos/farmacología , Regulación de la Expresión Génica/genética , Acetato de Glatiramer/uso terapéutico , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Estudios Prospectivos , Linfocitos T/metabolismo , Linfocitos T/fisiología
8.
Brain ; 142(9): 2756-2774, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31305892

RESUMEN

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of 'virtual hypoglycosis' induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.


Asunto(s)
Líquido Cefalorraquídeo/química , Metabolismo Energético/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Neuronas/efectos de los fármacos , Animales , Ceramidas/líquido cefalorraquídeo , Ceramidas/aislamiento & purificación , Ceramidas/toxicidad , Dinaminas/química , Glucosa/metabolismo , Glucosa/farmacología , Calor , Microscopía Intravital , Lactatos/metabolismo , Lactatos/farmacología , Lipidómica , Mitocondrias/metabolismo , Mitocondrias/patología , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Degeneración Nerviosa , Fosforilación , Procesamiento Proteico-Postraduccional , Ratas
9.
Proc Natl Acad Sci U S A ; 114(40): 10713-10718, 2017 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-28893978

RESUMEN

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.


Asunto(s)
Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Microbioma Gastrointestinal , Leucocitos Mononucleares/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T/inmunología , Animales , Células Cultivadas , Encefalomielitis Autoinmune Experimental/microbiología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Leucocitos Mononucleares/microbiología , Leucocitos Mononucleares/patología , Masculino , Ratones , Esclerosis Múltiple/microbiología , Esclerosis Múltiple/patología , Linfocitos T/microbiología , Linfocitos T/patología
10.
Glia ; 67(7): 1229-1239, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30734358

RESUMEN

Oligodendrocytes differentiate from oligodendrocyte progenitor cells (OPCs) in response to distinct extracellular signals. This process requires changes in gene expression resulting from the interplay between transcription factors and epigenetic modulators. Extracellular signals include chemical and physical stimuli. This review focuses on the signaling mechanisms activated in oligodendrocyte progenitors in response to mechanical forces. Of particular interest is a better understanding on how these forces are transduced into the OPC nuclei and subsequently reshape their epigenetic landscape. Here we will introduce the concept of epigenetic regulation of gene expression, first in general and then focusing on the oligodendrocyte lineage. We will then review the current literature on mechano-transduction in distinct cell types, followed by pathways identified in myelinating oligodendrocytes and their progenitors. Overall, the reader will be provided with a comprehensive review of the signaling pathways which allow oligodendrocyte progenitors to "sense" physical forces and transduce them into patterns of gene expression.


Asunto(s)
Núcleo Celular/metabolismo , Mecanotransducción Celular/fisiología , Células Precursoras de Oligodendrocitos/fisiología , Oligodendroglía/fisiología , Animales , Fenómenos Biomecánicos/fisiología , Diferenciación Celular/fisiología , Núcleo Celular/genética , Epigénesis Genética/fisiología , Expresión Génica , Humanos
11.
PLoS Biol ; 14(5): e1002467, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27213272

RESUMEN

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.


Asunto(s)
Sistema Nervioso Central/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Diferenciación Celular , Supervivencia Celular/genética , Cromatina/metabolismo , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factor 6 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Proteínas Proto-Oncogénicas/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Madre/metabolismo , alfa Carioferinas/metabolismo
12.
J Neurosci ; 37(31): 7547-7559, 2017 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-28663197

RESUMEN

Calcium-dependent nuclear export of histone deacetylase 1 (HDAC1) was shown previously to precede axonal damage in culture, but the in vivo relevance of these findings and the potential posttranslational modifications of HDAC1 remained elusive. Using acute hippocampal slices from mice of either sex with genetic conditional ablation of Hdac1 in CA1 hippocampal neurons (i.e., Camk2a-cre;Hdac1fl/fl), we show significantly diminished axonal damage in response to neurotoxic stimuli. The protective effect of Hdac1 ablation was detected also in CA3 neurons in Grik4-cre;Hdac1fl/f mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid. The amino acid residues modulating HDAC1 subcellular localization were identified by site-directed mutagenesis, which identified serine residues 421 and 423 as critical for its nuclear localization. The physiological phosphorylation of HDAC1 was decreased by neurotoxic stimuli, which stimulated the phosphatase enzymatic activity of calcineurin. Treatment of neurons with the calcineurin inhibitors FK506 or cyclosporin A resulted in nuclear accumulation of phospho-HDAC1 and was neuroprotective. Together, our data identify HDAC1 and the phosphorylation of specific serine residues in the molecule as potential targets for neuroprotection.SIGNIFICANCE STATEMENT The importance of histone deacetylation in normal brain functions and pathological conditions is unquestionable, yet the molecular mechanisms responsible for the neurotoxic potential of histone deacetylase 1 (HDAC1) and its subcellular localization are not fully understood. Here, we use transgenic lines to define the in vivo relevance of HDAC1 and identify calcineurin-dependent serine dephosphorylation as the signal modulating the neurotoxic role of HDAC1 in response to neurotoxic stimuli.


Asunto(s)
Histona Desacetilasa 1/metabolismo , Ácido Kaínico/envenenamiento , Neuronas/metabolismo , Serina/metabolismo , Fracciones Subcelulares/metabolismo , Animales , Histona Desacetilasa 1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neurotoxinas/envenenamiento , Fosforilación/efectos de los fármacos , Fracciones Subcelulares/efectos de los fármacos , Distribución Tisular
13.
Mult Scler ; 24(1): 69-74, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29307300

RESUMEN

Multiple sclerosis (MS) is a debilitating neurological disease whose onset and progression are influenced by the interplay of genetic and environmental factors. Epigenetic modifications, which include post-translational modification of the histones and DNA, are considered mediators of gene-environment interactions and a growing body of evidence suggests that they play an important role in MS pathology and could be potential therapeutic targets. Since epigenetic events regulate transcription of different genes in a cell type-specific fashion, we caution on the distinct functional consequences that targeting the same epigenetic modifications might have in distinct cell types. In this review, we primarily focus on the role of histone acetylation and DNA methylation on oligodendrocyte and T-cell function and its potential implications for MS. We find that decreased histone acetylation and increased DNA methylation in oligodendrocyte lineage (OL) cells enhance myelin repair, which is beneficial for MS, while the same epigenetic processes in T cells augment their pro-inflammatory phenotype, which can exacerbate disease severity. In conclusion, epigenetic-based therapies for MS may have great value but only when cellular specificity is taken into consideration.


Asunto(s)
Epigénesis Genética/inmunología , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Oligodendroglía/inmunología , Linfocitos T/inmunología , Acetilación , Animales , Encéfalo/inmunología , Metilación de ADN/inmunología , Histonas/metabolismo , Humanos
14.
Mult Scler ; 24(3): 262-267, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28080254

RESUMEN

BACKGROUND: People with multiple sclerosis (MS) have identified "wellness" and associated behaviors as a high priority based on "social media listening" undertaken by the National MS Society (i.e. the Society). OBJECTIVE: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. METHOD: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. RESULTS: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society's Wellness Research Working Group. CONCLUSION: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences.


Asunto(s)
Investigación Biomédica , Dieta Saludable , Ejercicio Físico , Esclerosis Múltiple , Sociedades Médicas , Humanos , Esclerosis Múltiple/dietoterapia , Esclerosis Múltiple/psicología , Esclerosis Múltiple/rehabilitación
15.
J Neurosci ; 36(3): 806-13, 2016 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-26791211

RESUMEN

Oligodendrocyte progenitors respond to biophysical or mechanical signals, and it has been reported that mechanostimulation modulates cell proliferation, migration, and differentiation. Here we report the effect of three mechanical stimuli on mouse oligodendrocyte progenitor differentiation and identify the molecular components of the linker of nucleoskeleton and cytoskeleton (LINC) complex (i.e., SYNE1) as transducers of mechanical signals to the nucleus, where they modulate the deposition of repressive histone marks and heterochromatin formation. The expression levels of LINC components increased during progenitor differentiation and silencing the Syne1 gene resulted in aberrant histone marks deposition, chromatin reorganization and impaired myelination. We conclude that spatial constraints, via the actin cytoskeleton and LINC complex, mediate nuclear changes in oligodendrocyte progenitors that favor a default pathway of differentiation. Significance statement: It is recognized that oligodendrocyte progenitors are mechanosensitive cells. However, the molecular mechanisms translating mechanical stimuli into oligodendrocyte differentiation remain elusive. This study identifies components of the mechanotransduction pathway in the oligodendrocyte lineage.


Asunto(s)
Núcleo Celular/metabolismo , Epigénesis Genética/fisiología , Mecanotransducción Celular/fisiología , Proteínas del Tejido Nervioso/biosíntesis , Proteínas Nucleares/biosíntesis , Oligodendroglía/fisiología , Animales , Núcleo Celular/genética , Proteínas del Citoesqueleto , Femenino , Masculino , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética
16.
J Neurosci ; 36(3): 957-62, 2016 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-26791223

RESUMEN

Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. Significance statement: Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under demyelinating conditions, successfully reversed social avoidance behavior in adult socially isolated mice. This was associated with enhanced myelination and oligodendrocyte differentiation in the prefrontal cortex through epigenetic regulation. Thus, enhancing myelination may be a potential means of reversing depressive-like social behavior.


Asunto(s)
Reacción de Prevención/fisiología , Clemastina/farmacología , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Corteza Prefrontal/metabolismo , Aislamiento Social , Animales , Reacción de Prevención/efectos de los fármacos , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Antagonistas Muscarínicos/farmacología , Fibras Nerviosas Mielínicas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos
17.
Development ; 141(12): 2414-28, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24917498

RESUMEN

In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-ß (Tgfß) family and signal canonically via Smads 1/5/8. Tgfß ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfß ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfß ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfß1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfß1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfß ligands and ActB together support oligodendrocyte development and myelin formation.


Asunto(s)
Activinas/metabolismo , Sistema Nervioso Central/embriología , Regulación del Desarrollo de la Expresión Génica , Oligodendroglía/citología , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Adhesión Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Técnicas de Cocultivo , Perfilación de la Expresión Génica , Humanos , Ligandos , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteína smad3/genética , Médula Espinal/embriología
18.
J Neurosci ; 35(1): 352-65, 2015 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-25568127

RESUMEN

In many cell types, differentiation requires an interplay between extrinsic signals and transcriptional changes mediated by repressive and activating histone modifications. Oligodendrocyte progenitors (OPCs) are electrically responsive cells receiving synaptic input. The differentiation of these cells into myelinating oligodendrocytes is characterized by temporal waves of gene repression followed by activation of myelin genes and progressive decline of electrical responsiveness. In this study, we used chromatin isolated from rat OPCs and immature oligodendrocytes, to characterize the genome-wide distribution of the repressive histone marks, H3K9me3 and H3K27me3, during differentiation. Although both marks were present at the OPC stage, only H3K9me3 marks (but not H3K27me3) were found to be increased during differentiation, at genes related to neuronal lineage and regulation of membrane excitability. Consistent with these findings, the levels and activity of H3K9 methyltransferases (H3K9 HMT), but not H3K27 HMT, increased more prominently upon exposure to oligodendrocyte differentiating stimuli and were detected in stage-specific repressive protein complexes containing the transcription factors SOX10 or YY1. Silencing H3K9 HMT, but not H3K27 HMT, impaired oligodendrocyte differentiation and functionally altered the response of oligodendrocytes to electrical stimulation. Together, these results identify repressive H3K9 methylation as critical for gene repression during oligodendrocyte differentiation.


Asunto(s)
Diferenciación Celular/fisiología , Cromatina/metabolismo , Histonas/metabolismo , Neurogénesis/fisiología , Oligodendroglía/metabolismo , Animales , Inmunoprecipitación de Cromatina/métodos , Femenino , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Embarazo , Ratas , Ratas Sprague-Dawley
19.
J Neurosci ; 35(33): 11482-99, 2015 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-26290228

RESUMEN

The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. However, comparatively little is known about the role of Sox2, especially during CNS remyelination. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination. SIGNIFICANCE STATEMENT: Understanding the mechanisms of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced in chronic demyelinating diseases such as multiple sclerosis. In this study, we describe the role of Sox2, a transcription factor widely implicated in stem cell biology, in CNS myelination and remyelination. We show how Sox2 is expressed in oligodendrocyte progenitor cells (OPCs) preparing to undergo differentiation, allowing them to undergo proliferation and priming them for subsequent differentiation. Although Sox2 is unlikely to be a direct therapeutic target, these data nevertheless provide more information on how OPC differentiation is controlled and therefore enriches our understanding of this important CNS regenerative process.


Asunto(s)
Enfermedades Desmielinizantes/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Factores de Transcripción SOXB1/metabolismo , Células Madre/metabolismo , Células Madre/patología , Animales , Diferenciación Celular , Células Cultivadas , Enfermedades Desmielinizantes/metabolismo , Femenino , Ratones , Ratones Transgénicos , Regeneración Nerviosa/fisiología , Ratas , Ratas Sprague-Dawley
20.
J Neurosci ; 35(34): 12002-17, 2015 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-26311780

RESUMEN

Lamin B1 is a component of the nuclear lamina and plays a critical role in maintaining nuclear architecture, regulating gene expression and modulating chromatin positioning. We have previously shown that LMNB1 gene duplications cause autosomal dominant leukodystrophy (ADLD), a fatal adult onset demyelinating disease. The mechanisms by which increased LMNB1 levels cause ADLD are unclear. To address this, we used a transgenic mouse model where Lamin B1 overexpression is targeted to oligodendrocytes. These mice showed severe vacuolar degeneration of the spinal cord white matter together with marked astrogliosis, microglial infiltration, and secondary axonal damage. Oligodendrocytes in the transgenic mice revealed alterations in histone modifications favoring a transcriptionally repressed state. Chromatin changes were accompanied by reduced expression of genes involved in lipid synthesis pathways, many of which are known to play important roles in myelin regulation and are preferentially expressed in oligodendrocytes. Decreased lipogenic gene expression resulted in a significant reduction in multiple classes of lipids involved in myelin formation. Many of these gene expression changes and lipid alterations were observed even before the onset of the phenotype, suggesting a causal role. Our findings establish, for the first time, a link between LMNB1 and lipid synthesis in oligodendrocytes, and provide a mechanistic framework to explain the age dependence and white matter involvement of the disease phenotype. These results have implications for disease pathogenesis and may also shed light on the regulation of lipid synthesis pathways in myelin maintenance and turnover. SIGNIFICANCE STATEMENT: Autosomal dominant leukodystrophy (ADLD) is fatal neurological disorder caused by increased levels of the nuclear protein, Lamin B1. The disease is characterized by an age-dependent loss of myelin, the fatty sheath that covers nerve fibers. We have studied a mouse model where Lamin B1 level are increased in oligodendrocytes, the cell type that produces myelin in the CNS. We demonstrate that destruction of myelin in the spinal cord is responsible for the degenerative phenotype in our mouse model. We show that this degeneration is mediated by reduced expression of lipid synthesis genes and the subsequent reduction in myelin enriched lipids. These findings provide a mechanistic framework to explain the age dependence and tissue specificity of the ADLD disease phenotype.


Asunto(s)
Envejecimiento/metabolismo , Enfermedades Desmielinizantes/metabolismo , Lamina Tipo B/biosíntesis , Metabolismo de los Lípidos/fisiología , Envejecimiento/genética , Animales , Enfermedades Desmielinizantes/genética , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Lámina Nuclear/genética , Lámina Nuclear/metabolismo , Oligodendroglía/metabolismo
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