Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 67
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 156(1-2): 277-90, 2014 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-24439382

RESUMEN

Central nervous system myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid impulse propagation. However, the underlying mechanisms of myelin wrapping have remained unclear. Using an integrative approach of live imaging, electron microscopy, and genetics, we show that new myelin membranes are incorporated adjacent to the axon at the innermost tongue. Simultaneously, newly formed layers extend laterally, ultimately leading to the formation of a set of closely apposed paranodal loops. An elaborated system of cytoplasmic channels within the growing myelin sheath enables membrane trafficking to the leading edge. Most of these channels close with ongoing development but can be reopened in adults by experimentally raising phosphatidylinositol-(3,4,5)-triphosphate levels, which reinitiates myelin growth. Our model can explain assembly of myelin as a multilayered structure, abnormal myelin outfoldings in neurological disease, and plasticity of myelin biogenesis observed in adult life.


Asunto(s)
Axones/metabolismo , Vaina de Mielina/metabolismo , Animales , Células Cultivadas , Sistema Nervioso Central/metabolismo , Ratones , Neuroglía/metabolismo , Oligodendroglía/metabolismo , Pez Cebra
2.
Glia ; 72(8): 1374-1391, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38587131

RESUMEN

Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also "funnel" lactate through their "myelinic" channels between gap junction-coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.


Asunto(s)
Axones , Glucólisis , L-Lactato Deshidrogenasa , Oligodendroglía , Animales , Oligodendroglía/metabolismo , Axones/metabolismo , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/genética , Glucólisis/fisiología , Ratones , Regulación hacia Abajo/fisiología , Ratones Endogámicos C57BL , Lactato Deshidrogenasa 5/metabolismo , Astrocitos/metabolismo , Astrocitos/ultraestructura , Ratones Transgénicos , Isoenzimas/metabolismo , Isoenzimas/genética , Uniones Comunicantes/metabolismo , Uniones Comunicantes/ultraestructura , Ratones Noqueados
3.
Mol Psychiatry ; 26(6): 1790-1807, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33564132

RESUMEN

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allows us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control. We report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells.


Asunto(s)
Hipoxia , Neuronas , Animales , Encéfalo , Hipocampo , Humanos , Ratones , Plasticidad Neuronal
4.
Mol Psychiatry ; 26(11): 6125-6148, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34188164

RESUMEN

While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.


Asunto(s)
Trastorno Autístico , Neuropéptidos , Animales , Trastorno Autístico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Corteza Cerebral/metabolismo , Humanos , Ratones , Neuronas/metabolismo , Neuropéptidos/metabolismo , Prosencéfalo/metabolismo , Factores de Transcripción/metabolismo
5.
Proc Natl Acad Sci U S A ; 115(30): E7184-E7192, 2018 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-29991598

RESUMEN

Neocortical pyramidal neurons express several distinct subtypes of voltage-gated Na+ channels. In mature cells, Nav1.6 is the dominant channel subtype in the axon initial segment (AIS) as well as in the nodes of Ranvier. Action potentials (APs) are initiated in the AIS, and it has been proposed that the high excitability of this region is related to the unique characteristics of the Nav1.6 channel. Knockout or loss-of-function mutation of the Scn8a gene is generally lethal early in life because of the importance of this subtype in noncortical regions of the nervous system. Using the Cre/loxP system, we selectively deleted Nav1.6 in excitatory neurons of the forebrain and characterized the excitability of Nav1.6-deficient layer 5 pyramidal neurons by patch-clamp and Na+ and Ca2+ imaging recordings. We now report that, in the absence of Nav1.6 expression, the AIS is occupied by Nav1.2 channels. However, APs are generated in the AIS, and differences in AP propagation to soma and dendrites are minimal. Moreover, the channels that are expressed in the AIS still show a clear hyperpolarizing shift in voltage dependence of activation, compared with somatic channels. The only major difference between Nav1.6-null and wild-type neurons was a strong reduction in persistent sodium current. We propose that the molecular environment of the AIS confers properties on whatever Na channel subtype is present and that some other benefit must be conferred by the selective axonal presence of the Nav1.6 channel.


Asunto(s)
Potenciales de Acción/fisiología , Axones/metabolismo , Canal de Sodio Activado por Voltaje NAV1.2/metabolismo , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , Neocórtex/metabolismo , Células Piramidales/metabolismo , Animales , Eliminación de Gen , Ratones , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Neocórtex/citología , Células Piramidales/citología
6.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-33804598

RESUMEN

We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive 'brain hardware upgrade' and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among other genes. We attested hypoxic cells by a transgenic reporter approach under the ubiquitous CAG promoter, with Hif-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. To specifically focus on the functional hypoxia of excitatory pyramidal neurons, here, we generated CaMKIIα-CreERT2-ODD::R26R-tdTomato mice. Behavioral challenges, light-sheet microscopy, immunohistochemistry, single-cell mRNA-seq, and neuronal cultures under normoxia or hypoxia served to portray these mice. Upon complex running wheel performance as the motor-cognitive task, a distinct increase in functional hypoxic neurons was assessed immunohistochemically and confirmed three-dimensionally. In contrast, fear conditioning as hippocampal stimulus was likely too short-lived to provoke neuronal hypoxia. Transcriptome data of hippocampus under normoxia versus inspiratory hypoxia revealed increases in CA1 CaMKIIα-neurons with an immature signature, characterized by the expression of Dcx, Tbr1, CaMKIIα, Tle4, and Zbtb20, and consistent with accelerated differentiation. The hypoxia reporter response was reproduced in vitro upon neuronal maturation. To conclude, task-associated activity triggers neuronal functional hypoxia as a local and brain-wide reaction mediating adaptive neuroplasticity. Hypoxia-induced genes such as EPO drive neuronal differentiation, brain maturation, and improved performance.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Cognición , Expresión Génica , Hipoxia/genética , Hipoxia/metabolismo , Neuronas/metabolismo , Animales , Encéfalo/fisiología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Células Cultivadas , Biología Computacional , Relación Dosis-Respuesta a Droga , Proteína Doblecortina , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Genes Reporteros , Inmunohistoquímica , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Células Piramidales/metabolismo , Tamoxifeno/farmacología , Transcriptoma
7.
EMBO J ; 35(18): 2008-25, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27497298

RESUMEN

Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly. In FBXO7 knockout mice, we find reduced proteasome activity and early-onset motor deficits together with premature death. In addition, we demonstrate that NEX (neuronal helix-loop-helix protein-1)-Cre-induced deletion of the FBXO7 gene in forebrain neurons or the loss of FBXO7 in tyrosine hydroxylase (TH)-positive neurons results in motor defects, reminiscent of the phenotype in PARK15 patients. Taken together, our study establishes a vital role for FBXO7 in neurons, which is required for proper motor control and accentuates the importance of FBXO7 in proteasome function.


Asunto(s)
Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Técnicas de Inactivación de Genes , Trastornos Parkinsonianos/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Ratones Noqueados , Procesamiento Proteico-Postraduccional , Ubiquitinación
8.
Int J Mol Sci ; 20(20)2019 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-31623261

RESUMEN

Hallmarks of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) include spinal cord (SC) inflammation, demyelination and axonal damage occurring approximately 5-8 weeks after classical intracerebral (i.c.) infection. The aim of this study was to elucidate the consequences of intraspinal (i.s.) TMEV infection and a direct comparison of classical i.c. and intraspinal infection. Swiss Jim Lambert (SJL)-mice were i.s. infected with the BeAn strain of TMEV. Clinical investigations including a scoring system and rotarod analysis were performed on a regular basis. Necropsies were performed at 3, 7, 14, 28 and 63 days post infection (dpi) following i.s. and at 4, 7, 14, 28, 56, 98, 147 and 196 dpi following i.c. infection. Serial sections of formalin-fixed, paraffin-embedded SC and peripheral nerves (PN) were investigated using hematoxylin and eosin (HE) and immunohistochemistry. I.s. infected mice developed clinical signs and a deterioration of motor coordination approximately 12 weeks earlier than i.c. infected animals. SC inflammation, demyelination and axonal damage occurred approximately 6 weeks earlier in i.s. infected animals. Interestingly, i.s. infected mice developed PN lesions, characterized by vacuolation, inflammation, demyelination and axonal damage, which was not seen following i.c. infection. The i.s. infection model offers the advantage of a significantly earlier onset of clinical signs, inflammatory and demyelinating SC lesions and additionally enables the investigation of virus-mediated PN lesions.


Asunto(s)
Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/patología , Poliomielitis/patología , Poliomielitis/virología , Theilovirus , Animales , Axones/patología , Encéfalo/patología , Encéfalo/virología , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Ratones , Ratones Transgénicos , Médula Espinal/patología , Médula Espinal/virología , Carga Viral
9.
PLoS Biol ; 13(3): e1002107, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25807062

RESUMEN

The development and regeneration of myelin by oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), requires profound changes in cell shape that lead to myelin sheath initiation and formation. Here, we demonstrate a requirement for the basal polarity complex protein Scribble in CNS myelination and remyelination. Scribble is expressed throughout oligodendroglial development and is up-regulated in mature oligodendrocytes where it is localised to both developing and mature CNS myelin sheaths. Knockdown of Scribble expression in cultured oligodendroglia results in disrupted morphology and myelination initiation. When Scribble expression is conditionally eliminated in the myelinating glia of transgenic mice, myelin initiation in CNS is disrupted, both during development and following focal demyelination, and longitudinal extension of the myelin sheath is disrupted. At later stages of myelination, Scribble acts to negatively regulate myelin thickness whilst suppressing the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAP) kinase pathway, and localises to non-compact myelin flanking the node of Ranvier where it is required for paranodal axo-glial adhesion. These findings demonstrate an essential role for the evolutionarily-conserved regulators of intracellular polarity in myelination and remyelination.


Asunto(s)
Sistema Nervioso Central/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Oligodendroglía/metabolismo , Animales , Polaridad Celular , Sistema Nervioso Central/ultraestructura , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Transgénicos , Oligodendroglía/ultraestructura , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal
10.
Nature ; 485(7399): 517-21, 2012 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-22622581

RESUMEN

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.


Asunto(s)
Axones/fisiología , Glucólisis , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Potenciales de Acción , Transferasas Alquil y Aril/deficiencia , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Animales , Encéfalo/citología , Encéfalo/metabolismo , Respiración de la Célula , Supervivencia Celular , Enfermedades Desmielinizantes/enzimología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Complejo IV de Transporte de Electrones/antagonistas & inhibidores , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Ácido Láctico/metabolismo , Espectroscopía de Resonancia Magnética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/enzimología , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oligodendroglía/citología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/enzimología , Protones , Células de Schwann/enzimología , Células de Schwann/metabolismo , Factores de Tiempo
11.
Glia ; 65(2): 342-359, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27807896

RESUMEN

NG2 expressing oligodendroglial precursor cells are ubiquitous in the central nervous system and the only cell type cycling throughout life. Previous fate mapping studies have remained inconsistent regarding the question whether NG2 cells are capable of generating certain types of neurons. Here, we use CNP-Cre mice to map the fate of a sub-population of NG2 cells assumed to be close to differentiation. When crossing these mice with the ROSA26/YFP Cre-reporter line we discovered large numbers of reporter-expressing pyramidal neurons in the piriform and dorsal cortex. In contrast, when using Z/EG reporter mice to track the fate of Cnp-expressing NG2 cells only oligodendroglial cells were found reporter positive. Using BrdU-based birth dating protocols and inducible NG2CreER:ROSA26/YFP mice we show that YFP positive neurons are generated from radial glial cells and that these radial glial cells display temporary and low level activity of certain oligodendroglial genes sufficient to recombine the Cre-inducible reporter gene in ROSA26/YFP but not in Z/EG mice. Taken together, we did not obtain evidence for generation of neurons from NG2 cells. Our results suggest that with an appropriate reporter system Cnp activity can be used to define a proliferative subpopulation of NG2 cells committed to generate oligodendrocytes. However, the strikingly different results obtained from ROSA26/YFP versus Z/EG mice demonstrate that the choice of Cre-reporter line can be of crucial importance for fate mapping studies and other applications of the Cre-lox technology. GLIA 2017;65:342-359.


Asunto(s)
2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/metabolismo , Antígenos/metabolismo , Encéfalo/citología , Diferenciación Celular/genética , Neuronas/fisiología , Oligodendroglía/fisiología , Proteoglicanos/metabolismo , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/genética , Animales , Animales Recién Nacidos , Antígenos/genética , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Bromodesoxiuridina/metabolismo , Recuento de Células , Linaje de la Célula , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica/genética , Genes Reporteros/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Proteoglicanos/genética
13.
Proc Natl Acad Sci U S A ; 111(36): 13205-10, 2014 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-25157163

RESUMEN

Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons. However, in contrast to previously published data, we demonstrate that PTEN is not a substrate of Nedd4-1 and Nedd4-2, and that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression.


Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Complejos Multiproteicos/metabolismo , Neuritas/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Axones/metabolismo , Corteza Cerebral/citología , Hipocampo/citología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones Noqueados , Modelos Biológicos , Morfogénesis , Ubiquitina-Proteína Ligasas Nedd4 , Poliubiquitina/metabolismo , Biosíntesis de Proteínas , Ubiquitinación
14.
Glia ; 64(11): 2025-40, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27470661

RESUMEN

Subtle white matter abnormalities have emerged as a hallmark of brain alterations in magnetic resonance imaging or upon autopsy of mentally ill subjects. However, it is unknown whether such reduction of white matter and myelin contributes to any disease-relevant phenotype or simply constitutes an epiphenomenon, possibly even treatment-related. Here, we have re-analyzed Mbp heterozygous mice, the unaffected parental strain of shiverer, a classical neurological mutant. Between 2 and 20 months of age, Mbp(+/-) versus Mbp(+/+) littermates were deeply phenotyped by combining extensive behavioral/cognitive testing with MRI, 1H-MR spectroscopy, electron microscopy, and molecular techniques. Surprisingly, Mbp-dependent myelination was significantly reduced in the prefrontal cortex. We also noticed a mild but progressive hypomyelination of the prefrontal corpus callosum and low-grade inflammation. While most behavioral functions were preserved, Mbp(+/-) mice exhibited defects of sensorimotor gating, as evidenced by reduced prepulse-inhibition, and a late-onset catatonia phenotype. Thus, subtle but primary abnormalities of CNS myelin can be the cause of a persistent cortical network dysfunction including catatonia, features typical of neuropsychiatric conditions. GLIA 2016;64:2025-2040.


Asunto(s)
Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Vaina de Mielina/metabolismo , Vías Nerviosas/patología , Sustancia Blanca/patología , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/genética , 2',3'-Nucleótido Cíclico 3'-Fosfodiesterasa/metabolismo , Factores de Edad , Animales , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/metabolismo , Microglía/patología , Microglía/ultraestructura , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Vaina de Mielina/genética , Vaina de Mielina/ultraestructura , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Embarazo , Inhibición Prepulso/genética , Reflejo de Sobresalto/genética , Sustancia Blanca/ultraestructura
15.
PLoS Biol ; 11(7): e1001604, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23874151

RESUMEN

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca²âº entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.


Asunto(s)
Exosomas/efectos de los fármacos , Neuronas/citología , Neurotransmisores/farmacología , Oligodendroglía/citología , Animales , Comunicación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Ácido Glutámico/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
16.
J Neurosci ; 33(2): 641-51, 2013 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-23303943

RESUMEN

Establishment of long-range fiber tracts by neocortical projection neurons is fundamental for higher brain functions. The molecular control of axon tract formation, however, is still poorly understood. Here, we have identified basic helix-loop-helix (bHLH) transcription factors Neurod2 and Neurod6 as key regulators of fasciculation and targeted axogenesis in the mouse neocortex. In Neurod2/6 double-mutant mice, callosal axons lack expression of the cell adhesion molecule Contactin2, defasciculate in the subventricular zone, and fail to grow toward the midline without forming Probst bundles. Instead, mutant axons overexpress Robo1 and follow random trajectories into the ipsilateral cortex. In contrast to long-range axogenesis, generation and maintenance of pyramidal neurons and initial axon outgrowth are grossly normal, suggesting that these processes are under distinct transcriptional control. Our findings define a new stage in corpus callosum development and demonstrate that neocortical projection neurons require transcriptional specification by neuronal bHLH proteins to execute an intrinsic program of remote connectivity.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Corteza Cerebral/fisiología , Proteínas del Tejido Nervioso/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Neuropéptidos/fisiología , Animales , Animales Recién Nacidos/fisiología , Axones/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Contactina 2/genética , Contactina 2/fisiología , Cuerpo Calloso/citología , Cuerpo Calloso/crecimiento & desarrollo , Cuerpo Calloso/fisiología , Electroporación , Embrión de Mamíferos/citología , Embrión de Mamíferos/fisiología , Genotipo , Glutamatos/fisiología , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Hibridación in Situ , Captura por Microdisección con Láser , Ratones , Fibras Nerviosas/fisiología , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/citología , Vías Nerviosas/crecimiento & desarrollo , Neurogénesis/fisiología , Reacción en Cadena de la Polimerasa , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Sinapsis/fisiología , Proteínas Roundabout
17.
Glia ; 62(6): 896-913, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24578301

RESUMEN

NG2 (nerve/glia antigen-2) is a type I transmembrane glycoprotein and also known as chondroitin sulfate proteoglycan 4. In the parenchyma of the central nervous system, NG2-expressing (NG2(+) ) cells have been identified as a novel type of glia with a strong potential to generate oligodendrocytes (OLs) in the developing white matter. However, the differentiation potential of NG2 glia remained controversial, largely attributable to shortcomings of transgenic mouse models used for fate mapping. To minimize these restrictions and to more faithfully mimic the endogenous NG2 expression in vivo, we generated a mouse line in which the open reading frame of the tamoxifen-inducible form of the Cre DNA recombinase (CreERT2) was inserted into the NG2 locus by homologous recombination. Results from this novel mouse line demonstrate that at different developmental stages of the brain, NG2(+) cells either stayed as NG2 glia or differentiated into OLs during the whole life span. Interestingly, when Cre activity was induced at embryonic stages, a significant number of reporter(+) astrocytes could be detected in the gray matter after birth. However, in other brain regions, such as olfactory bulb, brain stem, and cerebellum, all of the NG2 glia was restricted to the OL lineage. In addition, tamoxifen-sensitive and NG2 gene locus-dependent gene recombination could be detected in a small, but persistent population of cortical NeuN(+) neurons starting from the second postnatal week.


Asunto(s)
Antígenos/biosíntesis , Antígenos/genética , Diferenciación Celular/fisiología , Integrasas/biosíntesis , Integrasas/genética , Neuroglía/fisiología , Proteoglicanos/biosíntesis , Proteoglicanos/genética , Animales , Femenino , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligodendroglía/fisiología , Embarazo
18.
Eur J Immunol ; 43(1): 188-93, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23065717

RESUMEN

While the requirement for CD28 and its ligands for the generation and function of "natural" (n)Treg cells is well established, it has not been possible yet to investigate cell-intrinsic effects after interrupted CD28 expression. Here, we demonstrate a selective loss of Treg cells after disruption of the CD28 gene. The decline in Treg-cell number was accompanied by reduced homeostatic proliferation, probably due to lack of costimulation during self-antigen recognition, and by impaired Treg-cell function including downregulation of CTLA-4. The decline in Treg-cell number was unaffected by thymectomy or by the presence of CD28 expressing T cells within the same animal, indicating that impairment of peripheral homeostasis and function of nTreg cells by CD28 deletion is cell-intrinsic. In contrast, downregulation of CD25, the α chain of the IL-2R, did not occur in the presence of WT T cells, indicating that its expression does not depend on CD28 signals in cis.


Asunto(s)
Antígenos CD28/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Antígenos CD28/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Homeostasis , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
19.
EMBO Mol Med ; 16(3): 616-640, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38383802

RESUMEN

Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.


Asunto(s)
Artrogriposis , Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Fosfatidilinositol 3-Quinasas , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt , Roedores/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Serina-Treonina Quinasas TOR
20.
Nat Neurosci ; 27(9): 1668-1674, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39103558

RESUMEN

Amyloid-ß (Aß) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aß plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aß. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.


Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Ácido Aspártico Endopeptidasas , Neuronas , Oligodendroglía , Placa Amiloide , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Placa Amiloide/patología , Placa Amiloide/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA