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1.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760195

RESUMO

Neurodegenerative diseases are neurological disorders characterized by progressive neuronal degeneration, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. The neuronal damage caused by these diseases may be associated with abnormal alterations of connexins in glia. These changes may cause glia to lose their ability to support and protect neurons and induce abnormal increases in levels of ions and metabolites, such as calcium ions, glutamate and ATP, around neurons. These processes eventuallys lead to neuronal death. In the present review, the abnormal expression of connexin and its primary role in neurodegenerative diseases was investigated.


Assuntos
Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Conexinas/genética , Doença de Huntington/genética , Doença de Parkinson/genética , Trifosfato de Adenosina/genética , Envelhecimento/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Cálcio/metabolismo , Conexinas/metabolismo , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
2.
PLoS One ; 16(1): e0245171, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33493177

RESUMO

Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21-51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes.


Assuntos
Regulação da Expressão Gênica , Vírus da Influenza A Subtipo H1N1/metabolismo , Manganês/farmacologia , Meningite Viral/metabolismo , Neuroglia/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Substância Negra/metabolismo , Animais , Feminino , Masculino , Meningite Viral/patologia , Camundongos , Neuroglia/patologia , Neuroglia/virologia , Infecções por Orthomyxoviridae/patologia , RNA-Seq , Substância Negra/patologia , Substância Negra/virologia
3.
Environ Toxicol Pharmacol ; 83: 103584, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33460804

RESUMO

Airway pollution can affect the central nervous system, but whether this causes glial activation and inflammation in the nucleus of solitary tract (NTS) remains unclear. We used a rat model with exposure to diesel exhaust particulate matter (DEP) at 200 µg/m3 (low exposure) and 1000 µg/m3 (high exposure) for 14 days. Activation of microglia and astrocytes in the NTS was assessed using Iba-1 and glial fibrillary acidic protein (GFAP) staining. The expression of neurotrophic factors including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in the NTS were evaluated by immunofluorescence. Changes in the intracellular structure of NTS neurons were observed via electron microscopy. Inflammatory cytokines and oxidant stress levels in the medulla were also measured. Exposure to DEP can cause NTS inflammation as well as airway inflammation, especially in the H-exposure group. We showed that the numbers of microglia and astrocytes in the NTS, as well as NGF expression in the NTS, were significantly higher in both exposure groups than in controls, but BDNF or GDNF expression was not detected. Exposure to DEP induced ultrastructural changes in NTS neurons as reflected by endoplasmic reticulum dilation, ribosomal loss, mitochondrial vacuolization, and a sparse myelin sheath. Medulla inflammation and an imbalance of oxidants and antioxidants also resulted from exposure to DEP. The H-exposure group showed an imbalance of oxidants and antioxidants with decreased levels of SOD and GSH and increased levels of MDA and ROS compared to the control group (both p < 0.01) in the medulla. Inflammatory cytokines (IL-1ß, IL-6, and TNF-α) were also significantly increased in the H-exposure group. Fourteen days of exposure to DEP can affect the NTS neurons in rat. Glial activation and inflammation may play important roles in the response of the NTS to DEP.


Assuntos
Poluentes Atmosféricos/toxicidade , Encéfalo/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Emissões de Veículos/toxicidade , Administração por Inalação , Animais , Encéfalo/patologia , Encéfalo/ultraestrutura , Inflamação/etiologia , Inflamação/patologia , Pulmão/patologia , Masculino , Microscopia Eletrônica , Neuroglia/patologia , Neuroglia/ultraestrutura , Ratos Sprague-Dawley
4.
Methods Mol Biol ; 2191: 135-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32865743

RESUMO

In just over 10 years, the use of optogenetic technologies in neuroscience has become widespread, having today a tremendous impact on our understanding of brain function. An extensive number of studies have implemented a variety of tools allowing for the manipulation of neurons with light, including light-activated ion channels or G protein-coupled receptors, among other innovations. In this context, the proper calibration of photostimulation in vivo remains crucial to dissect brain circuitry or investigate the effect of neuronal activity on specific subpopulations of neurons and glia. Depending on the scientific question, the design of specific stimulation protocols must consider from the choice of the animal model to the light stimulation pattern to be delivered. In this chapter, we describe a detailed framework to investigate neuron-glia interactions in both mouse pups and adults using an optogenetic approach.


Assuntos
Channelrhodopsins/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Optogenética/métodos , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Humanos , Camundongos , Neuroglia/patologia , Neurônios/patologia , Técnicas de Patch-Clamp/métodos , Ratos
5.
Artigo em Inglês | MEDLINE | ID: mdl-33010453

RESUMO

Lipid droplets (LDs) are ubiquitous fat storage organelles composed of a neutral lipid core, comprising triacylglycerols (TAG) and sterol esters (SEs), surrounded by a phospholipid monolayer membrane with several decorating proteins. Recently, LD biology has come to the foreground of research due to their importance for energy homeostasis and cellular stress response. As aberrant LD accumulation and lipid depletion are hallmarks of numerous diseases, addressing LD biogenesis and turnover provides a new framework for understanding disease-related mechanisms. Here we discuss the potential role of LDs in neurodegeneration, while making some predictions on how LD imbalance can contribute to pathophysiology in the brain.


Assuntos
Doença de Alzheimer/metabolismo , Autofagia/genética , Demência Frontotemporal/metabolismo , Gotículas Lipídicas/metabolismo , Lipólise/genética , Atrofia Muscular Espinal/metabolismo , Sistema Nervoso/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Ésteres do Colesterol/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Regulação da Expressão Gênica , Humanos , Lisossomos/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fosfolipídeos/metabolismo , Triglicerídeos/metabolismo
6.
PLoS Biol ; 18(12): e3001008, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33315860

RESUMO

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.


Assuntos
Esclerose Múltipla/patologia , Nós Neurofibrosos/patologia , Substância Branca/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Axônios/patologia , Encéfalo/patologia , Sinapses Elétricas/patologia , Sinapses Elétricas/efeitos da radiação , Feminino , Humanos , Inflamação/patologia , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Bainha de Mielina/patologia , Neuroglia/patologia , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Nós Neurofibrosos/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/imunologia
7.
Int J Nanomedicine ; 15: 10113-10125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363370

RESUMO

Background: The excess production of reactive oxygen species (ROS) after traumatic spinal cord injury (TSCI) has been identified as a leading cause of secondary injury, which can significantly exacerbate acute damage in the injured spinal cord. Thus, scavenging of ROS has emerged as an effective route to ameliorate secondary spinal cord injury. Purpose: Selenium-doped carbon quantum dots (Se-CQDs) with the ability to scavenge reactive oxygen species were prepared and used for efficiently ameliorating secondary injury in TSCI. Methods: Water-soluble Se-CQDs were easily synthesized via hydrothermal treatment of l-selenocystine. The chemical structure, size, and morphology of the Se-CQDs were characterized in detail. The biocompatibility and protective effects of the Se-CQDs against H2O2-induced oxidative damage were investigated in vitro. Moreover, the behavioral test, bladder function, histological observation, Western blot were used to investigate the neuroprotective effect of Se-CQDs in a rat model of contusion TSCI. Results: The obtained Se-CQDs exhibited good biocompatibility and remarkable protective effect against H2O2-induced oxidative damage in astrocytes and PC12 cells. Moreover, Se-CQDs displayed marked anti-inflammatory and anti-apoptotic activities, which thereby reduced the formation of glial scars and increased the survival of neurons with unscathed myelin sheaths in vivo. As a result, Se-CQDs were capable of largely improving locomotor function of rats with TSCI. Conclusion: This study suggests that Se-CQDs can be used as a promising therapeutic platform for ameliorating secondary injury in TSCI.


Assuntos
Carbono/química , Pontos Quânticos/química , Espécies Reativas de Oxigênio/metabolismo , Selênio/farmacologia , Traumatismos da Medula Espinal/patologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Atividade Motora/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Pontos Quânticos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia
8.
PLoS One ; 15(9): e0238406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886667

RESUMO

INTRODUCTION: In cancer treatment an attempt has been made to pharmacologically regulate the proteasome functions, thus the aim was to test whether 20S proteasome chymotrypsin-like (ChT-L) activity has a role in glial brain tumors. Furthermore, we analyzed the correlation between proteasome activity and IL-8, CCL2, NF-κB1 and NF-κB2 concentrations, which impact on brain tumors has already been indicated. METHODS: Plasma 20S proteasome ChT-L activity was assayed using the fluorogenic peptide substrate Suc-Leu-Leu-Val-Tyr-AMC in the presence of SDS. IL-8, CCL2, NF-κB1 and NF-κB2 concentration was analyzed with the use of ELISA method. Immunohistochemistry for IDH1-R132H was done on 5-microns-thick formalin-fixed, paraffin-embedded tumor sections with the use of antibody specific for the mutant IDH1-R132H protein. Labelled streptavidin biotin kit was used as a detection system. RESULTS: Brain tumor patients had statistically higher 20S proteasome ChT-L activity (0.649 U/mg) compared to non-tumoral individuals (0.430 U/mg). IDH1 wild-type patients had statistically higher 20S proteasome ChT-L activity (1.025 U/mg) compared to IDH1 mutants (0.549 U/mg). 20S proteasome ChT-L activity in brain tumor patients who died as the consequence of a tumor (0.649) in the following 2 years was statistically higher compared to brain tumor patients who lived (0.430 U/mg). In brain tumor patients the 20S proteasome ChT-L activity positively correlated with IL-8 concentration. CONCLUSIONS: Elevated 20S proteasome ChT-L activity was related to the increased risk of death in glial brain tumor patients. A positive correlation between 20S proteasome ChT-L activity and IL-8 concentration may indicate the molecular mechanisms regulating glial tumor biology. Thus research on proteasomes may be important and should be carried out to verify if this protein complexes may represent a potential therapeutic target to limit brain tumor invasion.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Serina Endopeptidases/metabolismo , Adulto , Idoso , Biometria , Quimiocina CCL2/metabolismo , Quimotripsina/metabolismo , Cisteína Endopeptidases/metabolismo , Feminino , Glioma/patologia , Humanos , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/sangue , Proteólise , Serina Endopeptidases/sangue
9.
Mol Neurobiol ; 57(12): 5263-5275, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32869183

RESUMO

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças do Sistema Nervoso/etiologia , Pandemias , Pneumonia Viral/complicações , Animais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Efeito Citopatogênico Viral , Surtos de Doenças , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/imunologia , Humanos , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Proteínas do Tecido Nervoso/fisiologia , Doenças do Sistema Nervoso/imunologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/patologia , Neuroglia/virologia , Neurônios/patologia , Neurônios/virologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/imunologia , Receptores Virais/fisiologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Convulsões/etiologia , Convulsões/imunologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia
10.
Mol Cell ; 79(3): 376-389.e8, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640193

RESUMO

Activation of dual-specificity tyrosine-phosphorylation-regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl hydroxylation by PHD1 prolyl hydroxylase. Prolyl hydroxylation of DYRK1 initiates a cascade of events leading to the release of molecular constraints on von Hippel-Lindau (VHL) ubiquitin ligase tumor suppressor function. However, the proline residue of DYRK1 targeted by hydroxylation and the role of prolyl hydroxylation in tyrosine autophosphorylation of DYRK1 are unknown. We found that a highly conserved proline in the CMGC insert of the DYRK1 kinase domain is hydroxylated by PHD1, and this event precedes tyrosine autophosphorylation. Mutation of the hydroxylation acceptor proline precludes tyrosine autophosphorylation and folding of DYRK1, resulting in a kinase unable to preserve VHL function and lacking glioma suppression activity. The consensus proline sequence is shared by most CMGC kinases, and prolyl hydroxylation is essential for catalytic activation. Thus, formation of prolyl-hydroxylated intermediates is a novel mechanism of kinase maturation and likely a general mechanism of regulation of CMGC kinases in eukaryotes.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isoenzimas/genética , Prolina/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Células HEK293 , Xenoenxertos , Humanos , Hidroxilação , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Camundongos , Camundongos Nus , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Mutação , Neuroglia/metabolismo , Neuroglia/patologia , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
11.
Proc Natl Acad Sci U S A ; 117(29): 17269-17277, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611818

RESUMO

Traumatic brain injury (TBI) is the strongest environmental risk factor for the accelerated development of neurodegenerative diseases. There are currently no therapeutics to address this due to lack of insight into mechanisms of injury progression, which are challenging to study in mammalian models. Here, we have developed and extensively characterized a head-specific approach to TBI in Drosophila, a powerful genetic system that shares many conserved genes and pathways with humans. The Drosophila TBI (dTBI) device inflicts mild, moderate, or severe brain trauma by precise compression of the head using a piezoelectric actuator. Head-injured animals display features characteristic of mammalian TBI, including severity-dependent ataxia, life span reduction, and brain degeneration. Severe dTBI is associated with cognitive decline and transient glial dysfunction, and stimulates antioxidant, proteasome, and chaperone activity. Moreover, genetic or environmental augmentation of the stress response protects from severe dTBI-induced brain degeneration and life span deficits. Together, these findings present a tunable, head-specific approach for TBI in Drosophila that recapitulates mammalian injury phenotypes and underscores the ability of the stress response to mitigate TBI-induced brain degeneration.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/metabolismo , Drosophila/fisiologia , Neuroglia/metabolismo , Animais , Comportamento Animal , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Cabeça , Humanos , Masculino , Doenças Neurodegenerativas/metabolismo , Neuroglia/patologia , Estresse Fisiológico
12.
Am J Pathol ; 190(10): 2056-2066, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693061

RESUMO

Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, and infection. Postevent inflammation and neuroglial remodeling play a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using three different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques, we show that ocular trauma or surgery can cause robust infiltration of bone marrow-derived monocytes into the retina and subsequent neuroinflammation by up-regulation of Tnf, Il1b, and Il6 mRNA within 24 hours. This is accompanied by ganglion cell apoptosis and neurodegeneration. Prompt inhibition of tumor necrosis factor-α or IL-1ß markedly suppresses monocyte infiltration and ganglion cell loss. Thus, acute ocular injury (surgical or trauma) can lead to rapid neuroretinal inflammation and subsequent ganglion cell loss, the hallmark of glaucoma. Infiltrating monocytes play a central role in this process, likely amplifying the inflammatory cascade, aiding in the activation of retinal microglia. Prompt administration of cytokine inhibitors after ocular injury prevents this infiltration and ameliorates the damage to the retina-suggesting that it may be used prophylactically for neuroprotection against post-traumatic glaucoma.


Assuntos
Citocinas/antagonistas & inibidores , Glaucoma/metabolismo , Monócitos/patologia , Neuroglia/patologia , Retina/cirurgia , Animais , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Córnea/metabolismo , Córnea/patologia , Modelos Animais de Doenças , Glaucoma/patologia , Camundongos Transgênicos , Monócitos/metabolismo , Retina/metabolismo
13.
PLoS Genet ; 16(6): e1008841, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544203

RESUMO

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Bainha de Mielina/patologia , Neurogênese/genética , Proteínas Supressoras de Tumor/genética , Animais , Plexo Braquial/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Mutação da Fase de Leitura , Substância Cinzenta/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imagem por Ressonância Magnética , Neuroglia/patologia , Oligodendroglia , Nervo Isquiático/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Sequenciamento Completo do Exoma , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
14.
Brain Tumor Pathol ; 37(3): 100-104, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32535663

RESUMO

A subset of central nervous system neuroblastomas (CNS NB), rare primary embryonal CNS tumors, has been encompassed in CNS NB with FOXR2 activation (CNS NB-FOXR2) and usually shows the primitive neuronal architecture and occasional neurocytic differentiation. Here, we report a rare case of 3-year-old female with uncommon morphology of CNS embryonal tumor with FOXR2 activation presenting bidirectional differentiation to neurocytic small primitive cells and astrocytic spindle cells both of which are positive for synaptophysin and GFAP. Ultrastructural study also showed that there were presynaptic structure and intermediate filament in the tumor cells, suggesting glioneuronal differentiation. This case indicates the possibility of CNS neuroblastic tumor to differentiate neuronal and glial lineages.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fatores de Transcrição Forkhead/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroglia/patologia , Neurônios/patologia , Ativação Transcricional , Neoplasias Encefálicas/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Neuroblastoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X
15.
Int J Nanomedicine ; 15: 3649-3667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547020

RESUMO

Introduction: The polyphenolic spice and food coloring ingredient curcumin has beneficial effects in a broad variety of inflammatory diseases. Amongst them, curcumin has been shown to attenuate microglia reaction and prevent from glial scar formation in spinal cord and brain injuries. Methods: We developed a protocol for the efficient encapsulation of curcumin as a model for anti-inflammatory drugs yielding long-term stable, non-toxic liposomes with favorable physicochemical properties. Subsequently, we evaluate the effects of liposomal curcumin in experimental models for neuroinflammation and reactive astrogliosis. Results: We could show that liposomal curcumin can efficiently reduce the reactivity of human microglia and astrocytes and preserve tissue integrity of murine organotypic cortex slices. Discussion and Perspective: In perspective, we want to administer this curcumin formulation in brain implant coatings to prevent neuroinflammation and glial scar formation as foreign body responses of the brain towards implanted materials.


Assuntos
Encéfalo/patologia , Curcumina/uso terapêutico , Gliose/tratamento farmacológico , Inflamação/tratamento farmacológico , Neuroglia/patologia , Animais , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Encéfalo/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Lipossomos , Camundongos , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , Neuroglia/efeitos dos fármacos
16.
Rinsho Shinkeigaku ; 60(6): 420-424, 2020 Jun 06.
Artigo em Japonês | MEDLINE | ID: mdl-32435043

RESUMO

A 64-year-old woman visited our hospital with early-onset dementia and progressive gait disturbance. She had demonstrated a mild communication disorder at the age of ~40 years; however, her psychiatric symptoms at that time were mild and were not accompanied by social problems. At the age of 59, she presented with memory loss, visual hallucinations, and delusions. Over the following five years she developed gait difficulties that gradually deteriorated and suffered frequent falls. On admission, neurological examinations revealed severe pyramidal and extrapyramidal signs of akinetic mutism. MRI of the brain showed cerebral atrophy, enlarged lateral ventricles, thinning of the corpus callosum, and leukoencephalopathy in the frontal-parietal lobes. Additionally, CT revealed a small spotty calcification in the frontal subcortical white matter. Genetic analysis revealed a single-base substitution (c.2330G>A/p.R777Q) in exon 18 of the colony stimulating factor 1 receptor (CSF1R) gene, encoding the CSF1R protein. She was diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS). HDLS is included in the differential diagnosis of early-onset dementia and should be considered in patients with mild personality change and abnormal behavior in the early course of the illness.


Assuntos
Doenças dos Gânglios da Base/etiologia , Delusões/etiologia , Alucinações/etiologia , Leucoencefalopatias/complicações , Transtornos da Memória/etiologia , Neuroglia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose , Diagnóstico Diferencial , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Fatores de Tempo , Tomografia Computadorizada por Raios X
17.
Epilepsia ; 61(5): 1008-1018, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32347553

RESUMO

OBJECTIVE: To evaluate the interactions of metabolic neuronal-glial changes with the presence and hemispheric-side of hippocampal sclerosis (HS) and its potential role in predicting pharmacoresistance in temporal lobe epilepsy (TLE). METHODS: We included structural magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1 H-MRS) metabolic data for 91 patients with unilateral TLE and 50 healthy controls. We measured the values of total N-acetyl aspartate/total creatine (tNAA/tCr), glutamate/tCr (Glu/tCr), and myo-inositol/tCr (mIns/tCr). To assess the influence of the pharmacoresponse and hemispheric-side of HS on metabolic data, the relationship between clinical and MRI data, and the predictive value of NAA/Cr, we used analysis of variance/covariance and built a logistic regression model. We used bootstrap simulations to evaluate reproducibility. RESULTS: Bilateral tNAA/tCr reduction was associated with pharmacoresistance and with left HS, a decrease of Glu/tCr ipsilateral to the seizure focus was associated with pharmacoresistance, and ipsilateral mIns/tCr increase was related to pharmacoresistance and the presence of left HS. The logistic regression model containing clinical and 1 H-MRS data discriminated pharmacoresistance (area under the curve [AUC] = 0.78). However, the reduction of tNAA/tCr was the main predictor, with the odds 2.48 greater for pharmacoresistance. SIGNIFICANCE: Our study revealed a spectrum of neuronal-glial changes in TLE, which was associated with pharmacoresistance, being more severe in left-sided HS and less severe in MRI-negative TLE. These noninvasive, in vivo biomarkers provide valuable additional information about the interhemispheric differences in metabolic dysfunction, seizure burden, and HS, and may help to predict pharmacoresistance.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/patologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo/patologia , Neuroglia/patologia , Neurônios/patologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Creatina/metabolismo , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/patologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/diagnóstico por imagem , Humanos , Inositol/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , N-Metilaspartato/metabolismo , Neuroimagem , Espectroscopia de Prótons por Ressonância Magnética , Esclerose , Resultado do Tratamento , Adulto Jovem
18.
Neuron ; 106(4): 589-606.e6, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32169171

RESUMO

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) ß-oxidation pathway in peroxisomes and leads to H2O2 production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.


Assuntos
Acil-CoA Oxidase/genética , Axônios/enzimologia , Degeneração Neural/genética , Neuroglia/enzimologia , Animais , Axônios/patologia , Drosophila , Humanos , Camundongos , Mutação , Degeneração Neural/enzimologia , Neuroglia/patologia , Ratos
19.
Cancer Cell ; 37(3): 308-323.e12, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142668

RESUMO

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.


Assuntos
Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Glioma/tratamento farmacológico , Glioma/genética , Histonas/genética , Histonas/metabolismo , Humanos , Lactonas/farmacologia , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo
20.
PLoS Pathog ; 16(3): e1008371, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32130281

RESUMO

The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.


Assuntos
Plexo Corióideo/metabolismo , Células Epiteliais/metabolismo , Vesículas Extracelulares/metabolismo , Vírus JC/metabolismo , Leucoencefalopatia Multifocal Progressiva/metabolismo , Neuroglia/metabolismo , Receptores Virais/metabolismo , Linhagem Celular Transformada , Plexo Corióideo/patologia , Plexo Corióideo/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Vesículas Extracelulares/patologia , Vesículas Extracelulares/virologia , Humanos , Leucoencefalopatia Multifocal Progressiva/patologia , Neuroglia/patologia , Neuroglia/virologia
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