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1.
EMBO Rep ; 24(1): e55197, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36367221

RESUMEN

Transposable elements (TEs) are active in neuronal cells raising the question whether TE insertions contribute to risk of neuropsychiatric disease. While genome-wide association studies (GWAS) serve as a tool to discover genetic loci associated with neuropsychiatric diseases, unfortunately GWAS do not directly detect structural variants such as TEs. To examine the role of TEs in psychiatric and neurologic disease, we evaluated 17,000 polymorphic TEs and find 76 are in linkage disequilibrium with disease haplotypes (P < 10-6 ) defined by GWAS. From these 76 polymorphic TEs, we identify potentially causal candidates based on having insertions in genomic regions of regulatory chromatin and on having associations with altered gene expression in brain tissues. We show that lead candidate insertions have regulatory effects on gene expression in human neural stem cells altering the activity of a minimal promoter. Taken together, we identify 10 polymorphic TE insertions that are potential candidates on par with other variants for having a causal role in neurologic and psychiatric disorders.


Asunto(s)
Trastornos Mentales , Retroelementos , Humanos , Retroelementos/genética , Estudio de Asociación del Genoma Completo , Genoma , Sitios Genéticos , Trastornos Mentales/genética , Elementos Transponibles de ADN/genética , Evolución Molecular
2.
PLoS Pathog ; 17(2): e1009305, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33556144

RESUMEN

Ionizing radiation-induced tissue damage recruits monocytes into the exposed area where they are differentiated to macrophages. These implement phagocytic removal of dying cells and elicit an acute inflammatory response, but can also facilitate tumorigenesis due to production of anti-inflammatory cytokines. Using primary human monocyte-derived macrophages (MDMs) and the THP1 monocytic cell line, we demonstrate that gamma radiation triggers monocyte differentiation toward the macrophage phenotype with increased expression of type I interferons (IFN-I) and both pro- and anti-inflammatory macrophage activation markers. We found that these changes correlate with significantly upregulated expression of 622 retroelements from various groups, particularly of several clades of human endogenous retroviruses (HERVs). Elevated transcription was detected in both sense and antisense directions in the HERV subgroups tested, including the most genetically homogeneous clade HML-2. The level of antisense transcription was three- to five-fold higher than of the sense strand levels. Using a proximity ligation assay and immunoprecipitation followed by RNA quantification, we identified an increased amount of the dsRNA receptors MDA-5 and TLR3 bound to an equivalent number of copies of sense and antisense chains of HERVK HML-2 RNA. This binding triggered MAVS-associated signaling pathways resulting in increased expression of IFN-I and inflammation related genes that enhanced the cumulative inflammatory effect of radiation-induced senescence. HML-2 knockdown was accompanied with reduced expression and secretion of IFNα, pro-inflammatory (IL-1ß, IL-6, CCL2, CCL3, CCL8, and CCL20) and anti-inflammatory (IL10) modulators in irradiated monocytes and MDMs. Taken together, our data indicate that radiation stress-induced HERV expression enhances the IFN-I and cytokine response and results in increased levels of pro-inflammatory modulators along with expression of anti-inflammatory factors associated with the macrophage tumorigenic phenotype.


Asunto(s)
Retrovirus Endógenos/genética , Rayos gamma , Inflamación/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Retroelementos/genética , Diferenciación Celular , Citocinas/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Macrófagos/efectos de la radiación , Monocitos/metabolismo , Monocitos/efectos de la radiación , Transcriptoma
3.
Proc Natl Acad Sci U S A ; 117(30): 17842-17853, 2020 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-32669437

RESUMEN

Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical in maintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration.


Asunto(s)
Diferenciación Celular , Retrovirus Endógenos/fisiología , Neuronas/metabolismo , Transducción de Señal , Células Madre/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Biomarcadores , Diferenciación Celular/genética , Autorrenovación de las Células/genética , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Regulación Viral de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neuronas/citología , Unión Proteica , Células Madre/citología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas del Envoltorio Viral/genética
4.
Mol Psychiatry ; 24(1): 145-160, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30242227

RESUMEN

The assembly and maintenance of synapses are dynamic processes that require bidirectional contacts between the pre- and postsynaptic structures. A network of adhesion molecules mediate this physical interaction between neurons. How synapses are disassembled and if there are distinct mechanisms that govern the removal of specific adhesion molecules remain unclear. Here, we report isoform-specific proteolytic cleavage of neuroligin-3 in response to synaptic activity and protein kinase C signaling resulting in reduced synapse strength. Although neuroligin-1 and neuroligin-2 are not directly cleaved by this pathway, when heterodimerized with neuroligin-3, they too undergo proteolytic cleavage. Thus protein kinase C-dependent cleavage is mediated through neuroligin-3. Recent studies on glioma implicate the neuroligin-3 ectodomain as a mitogen. Here we demonstrate: (1) there are mechanisms governing specific adhesion molecule remodeling; (2) neuroligin-3 is a key regulator of neuroligin cleavage events; and (3) there are two cleavage pathways; basal and activity-dependent that produce the mitogenic form of neuroligin-3.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Sinapsis/fisiología , Animales , Adhesión Celular/fisiología , Células Cultivadas , Femenino , Células HEK293 , Células HeLa , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Factores de Crecimiento Nervioso/metabolismo , Neurregulina-1/metabolismo , Neuronas/metabolismo , Isoformas de Proteínas , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley
5.
Glia ; 66(11): 2503-2513, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30500113

RESUMEN

Neuroinflammatory diseases such as multiple sclerosis are characterized by infiltration of lymphocytes into the central nervous system followed by demyelination and axonal degeneration. While evidence suggests that activated T lymphocytes induce neurotoxicity and impair function of neural stem cells, the effect of T cells on oligodendrocyte progenitor cells (OPCs) is still uncertain, partly due to the difficulty in obtaining human OPCs. Here we studied the effect of activated T cells on OPCs using OPCs derived from human hematopoietic stem cells or from human fetal brain. OPCs were exposed to supernatants (sups) from activated T cells. Cell proliferation was determined by EdU incorporation and CellQuanti-Blue assays. Surprisingly, we found that sups from activated T cells induced OPC proliferation by regulating cell cycle progression. Vascular endothelial growth factor A (VEGF-A) transcripts were increased in T cells after activation. Immunodepletion of VEGF-A from activated T cell sups significantly attenuated its effect on OPC proliferation. Furthermore, VEGF receptor 2 (VEGFR2) was expressed on OPCs and its inhibition also attenuated activated T cell-induced OPC proliferation. Thus, activated T cells have a trophic role by promoting OPC proliferation via the VEGFR2 pathway.


Asunto(s)
Proliferación Celular/fisiología , Citocinas/metabolismo , Células Precursoras de Oligodendrocitos/fisiología , Regulación hacia Arriba/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Encéfalo/citología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Feto/anatomía & histología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Transfección , Regulación hacia Arriba/efectos de los fármacos , Urea/análogos & derivados , Urea/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
6.
Proc Natl Acad Sci U S A ; 112(8): 2551-6, 2015 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-25675530

RESUMEN

Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.


Asunto(s)
Trastorno Autístico/genética , Moléculas de Adhesión Celular Neuronal/genética , Potenciales Postsinápticos Excitadores , Mutación/genética , Proteína Quinasa C/metabolismo , Sinapsis/metabolismo , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular Neuronal/química , Células HEK293 , Humanos , Datos de Secuencia Molecular , Proteínas Mutantes/metabolismo , Neuronas/metabolismo , Fosforilación , Fosfotreonina/metabolismo , Ratas Sprague-Dawley
7.
Entropy (Basel) ; 20(9)2018 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-33265765

RESUMEN

A trailing-edge flap control strategy for mitigating rotor power fluctuations of a 5 MW offshore floating wind turbine is developed under turbulent wind inflow. The wind shear must be considered because of the large rotor diameter. The trailing-edge flap control strategy is based on the turbulent wind speed, the blade azimuth angle, and the platform motions. The rotor power is predicted using the free vortex wake method, coupled with the control strategy. The effect of the trailing-edge flap control on the rotor power is determined by a comparison with the rotor power of a turbine without a trailing-edge flap control. The optimal values of the three control factors are obtained. The results show that the trailing-edge flap control strategy is effective for improving the stability of the output rotor power of the floating wind turbine under the turbulent wind condition.

8.
J Neuroinflammation ; 14(1): 131, 2017 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-28655310

RESUMEN

BACKGROUND: The cause of neurodegeneration in progressive forms of multiple sclerosis is unknown. We investigated the impact of specific neuroinflammatory markers on human neurons to identify potential therapeutic targets for neuroprotection against chronic inflammation. METHODS: Surface immunocytochemistry directly visualized protease-activated receptor-1 (PAR1) and interleukin-1 (IL-1) receptors on neurons in human postmortem cortex in patients with and without neuroinflammatory lesions. Viability of cultured neurons was determined after exposure to cerebrospinal fluid from patients with progressive multiple sclerosis or purified granzyme B and IL-1ß. Inhibitors of PAR1 activation and of PAR1-associated second messenger signaling were used to elucidate a mechanism of neurotoxicity. RESULTS: Immunohistochemistry of human post-mortem brain tissue demonstrated cells expressing higher amounts of PAR1 near and within subcortical lesions in patients with multiple sclerosis compared to control tissue. Human cerebrospinal fluid samples containing granzyme B and IL-1ß were toxic to human neuronal cultures. Granzyme B was neurotoxic through activation of PAR1 and subsequently the phospholipase Cß-IP3 second messenger system. Inhibition of PAR1 or IP3 prevented granzyme B toxicity. IL-1ß enhanced granzyme B-mediated neurotoxicity by increasing PAR1 expression. CONCLUSIONS: Neurons within the inflamed central nervous system are imperiled because they express more PAR1 and are exposed to a neurotoxic combination of both granzyme B and IL-1ß. The effects of these inflammatory mediators may be a contributing factor in the progressive brain atrophy associated with neuroinflammatory diseases. Knowledge of how exposure to IL-1ß and granzyme B act synergistically to cause neuronal death yields potential novel neuroprotective treatments for neuroinflammatory diseases.


Asunto(s)
Supervivencia Celular/efectos de los fármacos , Granzimas/toxicidad , Interleucina-1beta/toxicidad , Receptor PAR-1/agonistas , Receptor PAR-1/metabolismo , Anciano , Anciano de 80 o más Años , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/patología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/patología
9.
medRxiv ; 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38826415

RESUMEN

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Discordant outcomes among dizygotic twins could be explained by genetic susceptibly or protection. Among several well-recognized threats to the developing brain, Zika is a mosquito-borne, positive-stranded RNA virus that was originally isolated in Uganda and spread to cause epidemics in Africa, Asia, and the Americas. In the Americas, the virus caused congenital Zika syndrome and a multitude of neurodevelopmental disorders. As of now, there is no preventative treatment or cure for the adverse outcomes caused by prenatal Zika infection. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium was initiated in 2016 to identify factors modulating prenatal brain injury and postnatal neurodevelopmental outcomes for Zika and other prenatal viral infections. Methods: The Consortium has pooled information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic data repository. This repository is being mined to search for modifiers of virally induced brain injury and developmental outcomes. Multilateral partnerships include commitments with Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), and Zika Instituto Fernandes Figueira (Brazil), in addition to the Centers for Disease Control and Prevention and the National Institutes of Health. Discussion: Our goal in bringing together these sets of patient data was to test the hypothesis that personal and populational genetic differences affect the severity of brain injury after a prenatal viral infection and modify neurodevelopmental outcomes. We have enrolled 4,102 mothers and 3,877 infants with 3,063 biological samples and clinical data covering over 80 phenotypic fields and 5,000 variables. There were several notable challenges in bringing together cohorts enrolled in different studies, including variability in the timepoints evaluated and the collected clinical data and biospecimens. Thus far, we have performed whole exome sequencing on 1,226 participants. Here, we present the Consortium's formation and the overarching study design. We began our investigation with prenatal Zika infection with the goal of applying this knowledge to other prenatal infections and exposures that can affect brain development.

10.
Neurobiol Dis ; 49: 169-76, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22940423

RESUMEN

PURPOSE: Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorder (HAND) is a neurodegenerative disease for which there is no available neuroprotective therapy. Viral proteins, such as Tat, have been implicated as agents of neurotoxicity via multiple mechanisms, including effects by directly binding to the NMDA receptor. We evaluated the ability of the immune response against Tat to modulate neurotoxicity at glutamate receptors. METHODS: Neurotoxicity was measured in primary neuronal-glial cultures and in hippocampal slice cultures. We used immunoprecipitation experiments to demonstrate interaction between Tat, NMDA receptor, and anti-Tat antibody. Using known structures of Tat and NMDA receptors, we developed a model of their interactions. RESULTS: Antibodies to Tat attenuated Tat-mediated neurotoxicity. Interestingly, Tat immune complexes also blocked neurotoxicity caused by NMDA receptor agonists but not kainate/AMPA receptor agonists. Neither Tat nor antibody alone blocked the excitotoxic effect, nor did an unrelated antigen-antibody complex. The protective effect of the Tat immune complexes was also lost when Tat was modified by nitrosylation or by using a deletion mutant of Tat. CONCLUSIONS: The ability of viral immune complexes to interact with NMDA receptors and prevent excitotoxicity represents a novel host defense mechanism. Host immune responses may influence host susceptibility to various effects of viral proteins, modulating HIV complications, such as onset of HAND. These observations provide rationale for development of vaccine therapies targeting Tat for prevention of HAND.


Asunto(s)
Complejo Antígeno-Anticuerpo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Animales , Anticuerpos/metabolismo , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/inmunología , Técnicas de Cocultivo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Humanos , Masculino , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Ratas Sprague-Dawley , Receptores AMPA/agonistas , Receptores AMPA/metabolismo , Receptores de Ácido Kaínico/agonistas , Receptores de Ácido Kaínico/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Eliminación de Secuencia , Técnicas de Cultivo de Tejidos , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética
11.
J Neurovirol ; 19(5): 418-31, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23982957

RESUMEN

Human immunodeficiency virus (HIV) infection-associated neurocognitive disorders is accompanied with brain atrophy. In these patients, impairment of adult neurogenesis and neurite outgrowth in the hippocampus may contribute to cognitive dysfunction. Although running exercises can enhance neurogenesis and normalize neurite outgrowth, the underlying molecular mechanisms are not well understood. The HIV envelope protein, gp120, has been shown to impair neurogenesis. Using a gp120 transgenic mouse model, we demonstrate that exercise stimulated neural progenitor cell (NPC) proliferation in the hippocampal dentate gyrus and increased the survival rate and generation of newborn cells. However, sustained exercise activity was necessary as the effects were reversed by detraining. Exercise also normalized dendritic outgrowth of neurons. Furthermore, it increased the expression of hippocampal brain-derived neurotrophic factor (BDNF) and normalized hyperactivation of cyclin-dependent kinase 5 (Cdk5). Hyperactivated Cdk5 or gp120 treatment led to aberrant neurite outgrowth and BDNF treatment normalized the neurite outgrowth in NPC cultures. These results suggest that sustained exercise has trophic activity on the neuronal lineage which is mediated by Cdk5 modulation of the BDNF pathway.


Asunto(s)
Complejo SIDA Demencia/genética , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Quinasa 5 Dependiente de la Ciclina/genética , Proteína gp120 de Envoltorio del VIH/genética , Neuritas/metabolismo , Condicionamiento Físico Animal , Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/patología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Proliferación Celular , Supervivencia Celular , Quinasa 5 Dependiente de la Ciclina/metabolismo , Giro Dentado/metabolismo , Giro Dentado/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuritas/patología , Neurogénesis/genética , Transgenes
12.
J Clin Invest ; 133(13)2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37395282

RESUMEN

Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor-like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2-specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.


Asunto(s)
Retrovirus Endógenos , Glioblastoma , Humanos , Animales , Ratones , Retrovirus Endógenos/genética , Glioblastoma/genética , Nicho de Células Madre , Provirus/genética
13.
Neurotherapeutics ; 19(4): 1313-1328, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35831747

RESUMEN

There is a continuing unmet medical need to develop neuroprotective strategies to treat neurodegenerative disorders. To address this need, we screened over 2000 compounds for potential neuroprotective activity in a model of oxidative stress and found that numerous antifungal agents were neuroprotective. Of the identified compounds, fluconazole was further characterized. Fluconazole was able to prevent neurite retraction and cell death in in vitro and in vivo models of toxicity. Fluconazole protected neurons in a concentration-dependent manner and exhibited efficacy against several toxic agents, including 3-nitropropionic acid, N-methyl D-aspartate, 6-hydroxydopamine, and the HIV proteins Tat and gp120. In vivo studies indicated that systemically administered fluconazole was neuroprotective in animals treated with 3-nitropropionic acid and prevented gp120-mediated neuronal loss. In addition to neuroprotection, fluconazole also induced proliferation of neural progenitor cells in vitro and in vivo. Fluconazole mediates these effects through upregulation and signaling via the insulin growth factor-1 receptor which results in decreased cAMP production and increased phosphorylation of Akt. Blockade of the insulin growth factor-1 receptor signaling with the selective inhibitor AG1024 abrogated the effects of fluconazole. Our studies suggest that fluconazole may be an attractive candidate for treatment of neurodegenerative diseases due to its protective properties against several categories of neuronal insults and its ability to spur neural progenitor cell proliferation.


Asunto(s)
Insulinas , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Animales , Receptor IGF Tipo 1/metabolismo , Neuroprotección , Fluconazol/farmacología , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt , Oxidopamina , Antifúngicos , Ácido D-Aspártico
14.
J Neurosci ; 30(14): 5020-7, 2010 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-20371822

RESUMEN

There is a great need for pharmacological approaches to enhance neural progenitor cell (NPC) function particularly in neuroinflammatory diseases with failed neuroregeneration. In diseases such as multiple sclerosis and stroke, T-cell infiltration occurs in periventricular zones where NPCs are located and is associated with irreversible neuronal loss. We studied the effect of T-cell activation on NPC functions. NPC proliferation and neuronal differentiation were impaired by granzyme B (GrB) released by the T-cells. GrB mediated its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltage-dependent potassium channel, Kv1.3. Importantly, blocking channel activity with margatoxin or blocking its expression reversed the inhibitory effects of GrB on NPCs. We have thus identified a novel pathway in neurogenesis. The increased expression of Kv1.3 in pathological conditions makes it a novel target for promoting neurorestoration.


Asunto(s)
Granzimas/metabolismo , Canal de Potasio Kv1.3/antagonistas & inhibidores , Canal de Potasio Kv1.3/fisiología , Activación de Linfocitos/fisiología , Inhibición Neural/fisiología , Neurogénesis/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Linfocitos T/metabolismo , Adulto , Animales , Células Cultivadas , Femenino , Feto , Humanos , Canal de Potasio Kv1.3/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Células Madre/efectos de los fármacos , Células Madre/enzimología , Células Madre/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimología
15.
Neurobiol Dis ; 41(3): 678-87, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21146610

RESUMEN

The prevalence of central nervous system (CNS) neurologic dysfunction associated with human immunodeficiency virus (HIV) infection continues to increase, despite the use of antiretroviral therapy. Previous work has focused on the deleterious effects of HIV on mature neurons and on development of neuroprotective strategies, which have consistently failed to show a meaningful clinical benefit. It is now well established that new neurons are continuously generated in discrete regions in the adult mammalian brain, and accumulating evidence supports important roles for these neurons in specific cognitive functions. In a transgenic mouse model of HIV neurologic disease with glial expression of the HIV envelope protein gp120, we demonstrate a significant reduction in proliferation of hippocampal neural progenitors in the dentate gyrus of adult animals, resulting in a dramatic decrease in the number of newborn neurons in the adult brain. We identify amplifying neural progenitor cells (ANPs) as the first class of progenitors affected by gp120, and we also demonstrate that newly generated neurons exhibit aberrant dendritic development. Furthermore, voluntary exercise and treatment with a selective serotonin reuptake inhibitor increase the ANP population and rescue the observed deficits in gp120 transgenic mice. Thus, during HIV infection, the envelope protein gp120 may potently inhibit adult hippocampal neurogenesis, and neurorestorative approaches may be effective in ameliorating these effects. Our study has significant implications for the development of novel therapeutic approaches for HIV-infected individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired.


Asunto(s)
Modelos Animales de Enfermedad , Infecciones por VIH/patología , Hipocampo/patología , Neurogénesis , Factores de Edad , Animales , Células Cultivadas , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/patología , Proteína gp120 de Envoltorio del VIH/biosíntesis , Infecciones por VIH/metabolismo , Infecciones por VIH/prevención & control , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/genética , Condicionamiento Físico Animal/fisiología
16.
Sci Rep ; 11(1): 12893, 2021 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-34145313

RESUMEN

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.


Asunto(s)
Transformación Celular Neoplásica/genética , Retrovirus Endógenos/genética , Tumor Rabdoide/etiología , Tumor Rabdoide/patología , Proteína SMARCB1/deficiencia , Eliminación de Secuencia , Activación Viral/genética , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular , Micropartículas Derivadas de Células/metabolismo , Susceptibilidad a Enfermedades , GTP Fosfohidrolasas/metabolismo , Regulación de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos , Transducción de Señal
17.
Neuron ; 106(5): 759-768.e7, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32243781

RESUMEN

Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Neuronas/metabolismo , Trastorno del Espectro Autista/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas , Discapacidad Intelectual/genética , Masculino , Mutación , Transporte de Proteínas/genética
18.
Exp Neurol ; 371: 114575, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37914567
19.
J Neuroimmunol ; 196(1-2): 124-32, 2008 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-18417225

RESUMEN

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.


Asunto(s)
Interleucina-17/metabolismo , Leucocitos Mononucleares/metabolismo , Esclerosis Múltiple/metabolismo , Mielitis Transversa/metabolismo , Adulto , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/citología , Células Cultivadas , Citocinas/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Feto , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Indoles , Interleucina-16/metabolismo , Leucocitos Mononucleares/química , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/patología , Mielitis Transversa/líquido cefalorraquídeo , Mielitis Transversa/patología , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Factores de Tiempo
20.
FASEB J ; 20(7): 906-15, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16675848

RESUMEN

It has been reported that extracellular matrix (ECM) molecules regulate monocyte activation by binding with a 67 kDa nonintegrin laminin receptor (LR). As microgliosis is a pivotal factor in propelling the progress of chronic neurodegeneration in the brain, we hypothesized that LR may regulate the microgliosis and subsequent neurotoxicity. Using 1-methyl-4-phenylpyridinium (MPP+) -treated C57 mice primary mesencephalic neuron-glia cultures as an in vitro Parkinson's disease (PD) model, we observed that MPP+ treatment increased LR expression only in the mixed neuron-glia but not in microglia-enriched or microglia-depleted cultures, indicating that MPP+-induced increase of LR expression is associated with neuron-microglia interaction. Using confocal microscopic examination, we found that LR was localized in the microglia, which were F4/80 positive. Treatment with the antibody (Ab) against LR (LR-Ab) or YIGSR, a synthetic pentapeptide inhibitor for LR, significantly attenuated the MPP+-increased F4/80 immunoreactivity (24 h) and dopaminergic (DA) neurotoxicity. LR-Ab also attenuated MPP+-increased microglial phagocytotic activity (48 h) and the superoxide production (4 days). Further study demonstrated that exogenous laminin (1-10 microg/ml) treatment induced microglial activation and DA neurotoxicity, in a dose-dependent manner, which was partially attenuated by the LR-Ab. We concluded that by regulating cell-ECM interaction, LR plays important roles in mediating microgliosis and subsequent DA neurotoxicity. Laminin is a potential ligand for activating this LR receptor. This study also suggests that laminin/LR is a potential target for developing new therapeutic drugs against neurodegenerative disorders such as PD.


Asunto(s)
1-Metil-4-fenilpiridinio/farmacología , Gliosis/metabolismo , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Receptores de Laminina/metabolismo , Animales , Anticuerpos/metabolismo , Células Cultivadas , Gliosis/patología , Laminina/farmacología , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Neuronas/metabolismo , Oligopéptidos/farmacología , Enfermedad de Parkinson/metabolismo , Superóxidos/metabolismo
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