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1.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
2.
Eur J Med Genet ; 64(9): 104282, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284163

RESUMO

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.


Assuntos
Agenesia do Corpo Caloso/genética , Axônios/patologia , Fatores de Transcrição Forkhead/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Oligodendroglia/patologia , Feto Abortado/metabolismo , Feto Abortado/patologia , Adulto , Agenesia do Corpo Caloso/patologia , Axônios/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Encéfalo/patologia , Códon sem Sentido , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Microcefalia/patologia , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Oligodendroglia/metabolismo , Linhagem , Gravidez , Síndrome
3.
Nat Genet ; 53(8): 1143-1155, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239132

RESUMO

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Cromatina/genética , Córtex Pré-Frontal/patologia , Sequências Reguladoras de Ácido Nucleico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Núcleo Celular/genética , Cromatina/metabolismo , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neuroglia/patologia , Oligodendroglia/patologia , Oligodendroglia/fisiologia , Córtex Pré-Frontal/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de Transcrição/genética
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208374

RESUMO

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1ß (IL-1ß) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1ß levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1ß induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.


Assuntos
Comportamento Animal , Encefalite/tratamento farmacológico , Mitocôndrias/patologia , Pioglitazona/uso terapêutico , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Encefalite/patologia , Feminino , Hipotermia Induzida , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Pioglitazona/farmacologia , Gravidez , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Perda de Peso/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
5.
J Cell Mol Med ; 25(11): 5150-5163, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33939286

RESUMO

Accordingly to its known function in corticospinal tract (CST) developmental growth, previous reports have shown an inhibitory role of Wnt5a in CST regeneration after spinal cord injury (SCI). Interestingly, it has been subsequently demonstrated that Wnt5a also modulates the developmental growth of non-CST axons and that different Wnt5a receptors are expressed in neurons, oligodendrocytes, NG2+ glial precursors and reactive microglia/macrophages and astrocytes after SCI. However, the role of Wnt5a in the response of these cell types, in the regeneration of non-CST axons and in functional recovery after SCI is currently unknown. To evaluate this, rats were subjected to spinal cord contusion and injected with a lentiviral vector generated to overexpress Wnt5a. Histological analyses were performed in spinal cord sections processed for the visualization of myelin, oligodendrocytes, neurons, microglia/macrophages, astrocytes, NG2+ glial precursors and serotonergic axons. Motor and bladder function recovery were also assessed. Further advancing our knowledge on the role of Wnt5a in SCI, we found that, besides its previously reported functions, Wnt5a overexpression elicits a reduction on neuronal cell density, the accumulation of NG2+ glial precursors and the descending serotonergic innervation in the affected areas, along with impairment of motor and bladder function recovery after SCI.


Assuntos
Bainha de Mielina/patologia , Regeneração Nervosa , Neurônios/patologia , Oligodendroglia/patologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Proteína Wnt-5a/metabolismo , Animais , Feminino , Bainha de Mielina/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Ratos , Ratos Wistar , Proteína Wnt-5a/genética
6.
PLoS One ; 16(5): e0243014, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983943

RESUMO

Multiple sclerosis (MS) is a complex, progressive neuroinflammatory disease associated with autoimmunity. Currently, effective therapeutic strategy was poorly found in MS. Experimental autoimmune encephalomyelitis (EAE) is widely used to study the pathogenesis of MS. Cumulative research have shown that bone marrow mesenchymal stem Cells (BMSCs) transplantation could treat EAE animal models, but the mechanism was divergent. Here, we systematically evaluated whether BMSCs can differentiate into neurons, astrocytes and oligodendrocytes to alleviate the symptoms of EAE mice. We used Immunofluorescence staining to detect MAP-2, GFAP, and MBP to evaluate whether BMSCs can differentiate into neurons, astrocytes and oligodendrocytes. The effect of BMSCs transplantation on inflammatory infiltration and demyelination in EAE mice were detected by Hematoxylin-Eosin (H&E) and Luxol Fast Blue (LFB) staining, respectively. Inflammatory factors expression was detected by ELISA and RT-qPCR, respectively. Our results showed that BMSCs could be induced to differentiate into neuron cells, astrocytes and oligodendrocyte in vivo and in vitro, and BMSCs transplanted in EAE mice were easier to differentiate than normal mice. Moreover, transplanted BMSCs reduced neurological function scores and disease incidence of EAE mice. BMSCs transplantation alleviated the inflammation and demyelination of EAE mice. Finally, we found that BMSCs transplantation down-regulated the levels of pro-inflammatory factors TNF-α, IL-1ß and IFN-γ, and up-regulated the levels of anti-inflammatory factors IL-10 and TGF-ß. In conclusion, this study found that BMSCs could alleviate the inflammatory response and demyelination in EAE mice, which may be achieved by the differentiation of BMSCs into neurons, astrocytes and oligodendrocytes in EAE mice.


Assuntos
Astrócitos/citologia , Diferenciação Celular , Encefalomielite Autoimune Experimental/terapia , Inflamação/patologia , Células-Tronco Mesenquimais/citologia , Neurônios/citologia , Oligodendroglia/citologia , Oligodendroglia/patologia , Animais , Células Cultivadas , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Masculino , Transplante de Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL
7.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922276

RESUMO

Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.


Assuntos
Astrócitos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Mucolipidoses/patologia , Células-Tronco Neurais/patologia , Neuraminidase/metabolismo , Oligodendroglia/patologia , Teratoma/patologia , Astrócitos/metabolismo , Autofagia , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lisossomos , Mucolipidoses/genética , Mucolipidoses/metabolismo , Mutação , Células-Tronco Neurais/metabolismo , Neuraminidase/genética , Oligodendroglia/metabolismo , Fenótipo , Teratoma/genética , Teratoma/metabolismo
8.
Oxid Med Cell Longev ; 2021: 5521503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815654

RESUMO

Background: Bu Shen Yi Sui capsule (BSYS) is a traditional Chinese medicine prescription that has shown antineuroinflammatory and neuroprotective effects in treating multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Microglia play an important role in neuroinflammation. The M1 phenotype of microglia is involved in the proinflammatory process of the disease, while the M2 phenotype plays an anti-inflammatory role. Promoting the polarization of microglia to M2 in MS/EAE is a promising therapeutic strategy. This study is aimed at exploring the effects of BSYS on microglial polarization in mice with EAE. Methods: The EAE model was established by the intraperitoneal injection of pertussis toxin and subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG)35-55 in C57BL/6J mice. The mice were treated with BSYS (3.02 g/kg), FTY720 (0.3 mg/kg), or distilled water by intragastric administration. H&E and LFB staining, transmission electron microscopy, qRT-PCR, immunofluorescence, ELISA, fluorescence in situ hybridization, and western blotting were used to detect the histological changes in myelin, microglial M1/M2 polarization markers, and the expression of key genes involved in EAE. Results and Conclusions. BSYS treatment of EAE mice increased the body weight, decreased the clinical score, and reduced demyelination induced by inflammatory infiltration. BSYS also inhibited the mRNA expression of M1 microglial markers while increasing the mRNA level of M2 markers. Additionally, BSYS led to a marked decrease in the ratio of M1 microglia (iNOS+/Iba1+) and an obvious increase in the number of M2 microglia (Arg1+/Iba1+). In the EAE mouse model, miR-124 expression was decreased, and miR-155 expression was increased, while BSYS treatment significantly reversed this effect and modulated the levels of C/EBP α, PU.1, and SOCS1 (target genes of miR-124 and miR-155). Therefore, the neuroprotective effect of BSYS against MS/EAE was related to promoting microglia toward M2 polarization, which may be correlated with changes in miR-124 and miR-155 in vivo.


Assuntos
Encéfalo/patologia , Doenças Desmielinizantes/genética , Medicamentos de Ervas Chinesas/farmacologia , Encefalomielite Autoimune Experimental/genética , Inflamação/patologia , MicroRNAs/metabolismo , Microglia/patologia , Animais , Peso Corporal/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Cápsulas , Diferenciação Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/patologia , Exossomos/metabolismo , Feminino , Inflamação/genética , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/genética , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Fenótipo , Proteínas Proto-Oncogênicas/metabolismo , Medula Espinal/patologia , Transativadores/metabolismo , Regulação para Cima/genética
9.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925469

RESUMO

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.


Assuntos
Encefalite/metabolismo , Esclerose Múltipla/patologia , Receptores Acoplados a Proteínas G/metabolismo , Substância Branca/patologia , Adulto , Encefalite/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substância Branca/metabolismo
10.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33918092

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neuron degeneration leads to muscle weakness, progressive paralysis, and death within 3-5 years of diagnosis. Currently, the cause of ALS is unknown but, as with several neurodegenerative diseases, the potential role of neuroinflammation has become an increasingly popular hypothesis in ALS research. Indeed, upregulation of neuroinflammatory factors have been observed in both ALS patients and animal models. One such factor is the inflammatory inducer NF-κB. Besides its connection to inflammation, NF-κB activity can be linked to several genes associated to familial forms of ALS, and many of the environmental risk factors of the disease stimulate NF-κB activation. Collectively, this has led many to hypothesize that NF-κB proteins may play a role in ALS pathogenesis. In this review, we discuss the genetic and environmental connections between NF-κB and ALS, as well as how this pathway may affect different CNS cell types, and finally how this may lead to motor neuron degeneration.


Assuntos
Esclerose Amiotrófica Lateral/etiologia , Esclerose Amiotrófica Lateral/metabolismo , Suscetibilidade a Doenças , NF-kappa B/metabolismo , Alelos , Esclerose Amiotrófica Lateral/patologia , Animais , Biomarcadores , Meio Ambiente , Ativação Enzimática , Predisposição Genética para Doença , Variação Genética , Humanos , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia
11.
Immunology ; 164(1): 90-105, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33880776

RESUMO

Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Although Fc fragments derived from IVIG have shown efficacy in controlling immune thrombocytopenia in children, the mechanisms of action are unclear and controversial. The aim of this study was to dissect IVIG effector mechanisms using further adapted Fc fragments on demyelination in an ex vivo model of the central nervous system-immune interface. Using organotypic cerebellar slice cultures (OSCs) from transgenic mice, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective effects of adapted Fc fragments were assessed by live imaging of green fluorescent protein expression, immunohistochemistry and confocal microscopy. Cysteine- and glycan-adapted Fc fragments protected OSC from demyelination in a dose-dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement-mediated oligodendroglia damage. Transcriptome analysis ruled out signatures associated with inflammatory or innate immune responses. Taken together, our findings show that recombinant biomimetics can be made that are at least two hundred-fold more effective than IVIG in controlling demyelination by anti-MOG antibodies.


Assuntos
Autoanticorpos/uso terapêutico , Cerebelo/patologia , Doenças Desmielinizantes/terapia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoglobulina G/uso terapêutico , Oligodendroglia/patologia , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Autoanticorpos/genética , Cerebelo/efeitos dos fármacos , Doenças Desmielinizantes/imunologia , Células HEK293 , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/genética , Imunoglobulinas Intravenosas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Oligodendroglia/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Proteínas Recombinantes de Fusão/genética
12.
Epilepsia ; 62(6): 1429-1441, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33884614

RESUMO

OBJECTIVE: We aimed to better characterize the magnetic resonance imaging (MRI) findings of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE), a rare clinicopathological entity associated with pharmacoresistance recently described in patients with frontal lobe epilepsy. METHODS: We studied 12 patients who underwent epilepsy surgery and whose surgical specimens showed histopathological findings of MOGHE, characterized by preserved cortical lamination, blurred gray-white matter interface due to increased number of oligodendrocytes, and heterotopic neurons in the white matter. The age at MRI evaluation ranged from 11 to 58 years, except for one 4.5-year-old patient. RESULTS: Following a detailed MRI analysis using an in-house protocol, we found abnormalities in all cases. The lesion was circumscribed in the frontal lobe in six (50%) and in the temporal lobe in three (25%) patients. In the remaining three patients (25%), the lesion was multilobar (frontotemporal and temporoparieto-occipital). Cortical thickening was mild in all patients, except in the 4.5-year-old patient, who had pronounced cortical thickening and white matter blurring. We also identified cortical/subcortical hyperintense T2/fluid-attenuated inversion recovery signal associated with gray/white matter blurring in all but one patient. When present, cleft cortical dimple, and deep sulci aided in localizing the lesion. Overall, the MRI findings were like those in focal cortical dysplasia (FCD) Type IIa. Surgical outcome was excellent in five patients (Engel Class I in 25% and II in 17%). The remaining seven patients (58%) had worthwhile seizure reduction (Engle Class III). Incomplete lesion resection was significantly associated with worse outcomes. SIGNIFICANCE: MRI findings associated with MOGHE are similar to those described in FCD Type IIa. Although more frequent in the frontal lobe, MOGHE also occurred in the temporal lobe or involved multiple lobes. Multilobar or extensive MOGHE MRI lesions are associated with less favorable surgical outcomes. Because this is a rare condition, multicenter studies are necessary to characterize MOGHE further.


Assuntos
Epilepsia do Lobo Frontal/diagnóstico por imagem , Epilepsia do Lobo Frontal/patologia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Oligodendroglia/patologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia , Epilepsia do Lobo Frontal/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/cirurgia , Pessoa de Meia-Idade , Neurônios/patologia , Procedimentos Neurocirúrgicos , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Adulto Jovem
13.
Biomolecules ; 11(3)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803137

RESUMO

Lysosomes are cellular organelles that contain various acidic digestive enzymes. Despite their small size, they have multiple functions. Lysosomes remove or recycle unnecessary cell parts. They repair damaged cellular membranes by exocytosis. Lysosomes also sense cellular energy status and transmit signals to the nucleus. Glial cells are non-neuronal cells in the nervous system and have an active role in homeostatic support for neurons. In response to dynamic cues, glia use lysosomal pathways for the secretion and uptake of regulatory molecules, which affect the physiology of neighboring neurons. Therefore, functional aberration of glial lysosomes can trigger neuronal degeneration. Here, we review lysosomal functions in oligodendrocytes, astrocytes, and microglia, with emphasis on neurodegeneration.


Assuntos
Lisossomos/metabolismo , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/metabolismo , Neuroglia/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Humanos , Oligodendroglia/metabolismo , Oligodendroglia/patologia
14.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809224

RESUMO

The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient's lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Descoberta de Drogas , Remielinização/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/patologia , Humanos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Regeneração Nervosa/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia
15.
Nat Commun ; 12(1): 2184, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846316

RESUMO

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.


Assuntos
Neoplasias Encefálicas/patologia , Diferenciação Celular , Glioblastoma/patologia , Substância Branca/patologia , Animais , Neoplasias Encefálicas/ultraestrutura , Linhagem da Célula , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/ultraestrutura , Camundongos Endogâmicos NOD , Camundongos SCID , Bainha de Mielina/metabolismo , Oligodendroglia/patologia , Fatores de Transcrição SOXE/metabolismo , Transcriptoma/genética , Regulação para Cima/genética
16.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671716

RESUMO

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.


Assuntos
Efrinas/metabolismo , Esclerose Múltipla/imunologia , Oligodendroglia/patologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Ratos , Subpopulações de Linfócitos T/imunologia
17.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33593907

RESUMO

The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human. The method uses a simple staining procedure involving the lipophilic dye Nile Red, whose fluorescence spectrum varies according to the chemical polarity of the microenvironment into which the dye embeds. Nile Red spectroscopy identified histologically intact yet biochemically altered myelin in prelesioned tissues, including mouse white matter following subdemyelinating cuprizone intoxication, as well as normal-appearing white matter in multiple sclerosis brain. Nile Red spectroscopy offers a relatively simple yet highly sensitive technique for detecting subtle myelin changes.


Assuntos
Esclerose Múltipla/patologia , Bainha de Mielina/química , Oligodendroglia/patologia , Oxazinas/química , Espectrometria de Fluorescência/métodos , Idoso , Animais , Estudos de Casos e Controles , Linhagem Celular , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Corantes Fluorescentes , Substância Cinzenta/química , Substância Cinzenta/citologia , Humanos , Lipídeos/química , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Oligodendroglia/química , Substância Branca/química , Substância Branca/citologia
18.
Cell Death Dis ; 12(2): 166, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558485

RESUMO

A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1ß from P1 to P5. In the IL-1ß-treated animals, we observed the upregulation of Tlr3, IL-1ß, IFN-ß, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.


Assuntos
Diferenciação Celular , Proliferação de Células , Encefalite/metabolismo , Leucoencefalopatias/metabolismo , Oligodendroglia/metabolismo , Receptor 3 Toll-Like/metabolismo , Substância Branca/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/genética , Encefalite/imunologia , Encefalite/patologia , Feminino , Mediadores da Inflamação/metabolismo , Leucoencefalopatias/genética , Leucoencefalopatias/imunologia , Leucoencefalopatias/patologia , Masculino , Camundongos , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/imunologia , Oligodendroglia/patologia , Poli I-C/farmacologia , Gravidez , Nascimento Prematuro , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Receptor 3 Toll-Like/agonistas , Substância Branca/efeitos dos fármacos , Substância Branca/imunologia , Substância Branca/patologia
19.
Nat Neurosci ; 24(2): 234-244, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33526922

RESUMO

Fibrosis is a common pathological response to inflammation in many peripheral tissues and can prevent tissue regeneration and repair. Here, we identified persistent fibrotic scarring in the CNS following immune cell infiltration in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Using lineage tracing and single-cell sequencing in EAE, we determined that the majority of the fibrotic scar is derived from proliferative CNS fibroblasts, not pericytes or infiltrating bone marrow-derived cells. Ablating proliferating fibrotic cells using cell-specific expression of herpes thymidine kinase led to an increase in oligodendrocyte lineage cells within the inflammatory lesions and a reduction in motor disability. We further identified that interferon-gamma pathway genes are enriched in CNS fibrotic cells, and the fibrotic cell-specific deletion of Ifngr1 resulted in reduced fibrotic scarring in EAE. These data delineate a framework for understanding the CNS fibrotic response.


Assuntos
Barreira Hematoencefálica/patologia , Encefalomielite Autoimune Experimental/patologia , Fibroblastos/patologia , Fibrose/patologia , Infiltração de Neutrófilos , Medula Espinal/patologia , Animais , Camundongos , Oligodendroglia/patologia
20.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33514021

RESUMO

Apolipoprotein D (Apo D) overexpression is a general finding across neurodegenerative conditions so the role of this apolipoprotein in various neuropathologies such as multiple sclerosis (MS) has aroused a great interest in last years. However, its mode of action, as a promising compound for the development of neuroprotective drugs, is unknown. The aim of this work was to address the potential of Apo D to prevent the action of cuprizone (CPZ), a toxin widely used for developing MS models, in oligodendroglial and neuroblastoma cell lines. On one hand, immunocytochemical quantifications and gene expression measures showed that CPZ compromised neural mitochondrial metabolism but did not induce the expression of Apo D, except in extremely high doses in neurons. On the other hand, assays of neuroprotection demonstrated that antipsychotic drug, clozapine, induced an increase in Apo D synthesis only in the presence of CPZ, at the same time that prevented the loss of viability caused by the toxin. The effect of the exogenous addition of human Apo D, once internalized, was also able to directly revert the loss of cell viability caused by treatment with CPZ by a reactive oxygen species (ROS)-independent mechanism of action. Taken together, our results suggest that increasing Apo D levels, in an endo- or exogenous way, moderately prevents the neurotoxic effect of CPZ in a cell model that seems to replicate some features of MS which would open new avenues in the development of interventions to afford MS-related neuroprotection.


Assuntos
Apolipoproteínas D/genética , Doenças Desmielinizantes/genética , Esclerose Múltipla/genética , Oligodendroglia/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/terapia , Modelos Animais de Doenças , Humanos , Camundongos , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Fármacos Neuroprotetores/uso terapêutico , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Espécies Reativas de Oxigênio/metabolismo
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