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1.
Redox Biol ; 49: 102221, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34952462

RESUMEN

Redox regulation of specific cysteines via oxidoreductases of the thioredoxin family is increasingly being recognized as an important signaling pathway. Here, we demonstrate that the cytosolic isoform of the vertebrate-specific oxidoreductase Glutaredoxin 2 (Grx2c) regulates the redox state of the transcription factor SP-1 and thereby its binding affinity to both the promoter and an enhancer region of the CSPG4 gene encoding chondroitin sulfate proteoglycan nerve/glial antigen 2 (NG2). This leads to an increased number of NG2 glia during in vitro oligodendroglial differentiation and promotes migration of these wound healing cells. On the other hand, we found that the same mechanism also leads to increased invasion of glioma tumor cells. Using in vitro (human cell lines), ex vivo (mouse primary cells), and in vivo models (zebrafish), as well as glioblastoma patient tissue samples we provide experimental data highlighting the Yin and Yang of redox signaling in the central nervous system and the enzymatic Taoism of Grx2c.


Asunto(s)
Glioma , Glutarredoxinas , Animales , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Glioma/genética , Glioma/metabolismo , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Neuroglía/metabolismo , Filosofías Religiosas , Cicatrización de Heridas/genética , Pez Cebra/metabolismo
2.
Brain Commun ; 3(4): fcab229, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34755108

RESUMEN

The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse. Cox proportional hazard models were used to analyse the probability of developing confirmed progression independent of relapse activity depending on both disease and natalizumab treatment duration. Among the 184 patients identified, 44 (24%) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset. Time to confirmed progression independent of relapse activity was not affected by Expanded Disability Status Scale at natalizumab onset (categorized by Expanded Disability Status Scale score ≤3.5 versus >3.5) nor by duration of disease nor by duration of therapy. Confirmed progression independent of relapse activity occurred earlier in the disease course in patients with an earlier natalizumab therapy onset with regard to disease duration. A stepwise forward regression analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005). Taken together, confirmed progression independent of relapse activity occurs in a substantial proportion of patients on long-term natalizumab treatment and independent of Expanded Disability Status Scale score at natalizumab onset. Our findings suggest that patients who are initiated on natalizumab early during disease course, usually in order to treat an aggressive clinical phenotype, have a higher risk of early confirmed progression independent of relapse activity.

3.
Artículo en Inglés | MEDLINE | ID: mdl-34045307

RESUMEN

OBJECTIVE: Retinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses. METHODS: In this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing. RESULTS: A total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (ß = -0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively. CONCLUSION: In patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination.


Asunto(s)
Disfunción Cognitiva , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Neuronas Retinianas/patología , Adolescente , Adulto , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/complicaciones , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Pruebas Neuropsicológicas , Tomografía de Coherencia Óptica , Adulto Joven
4.
Artículo en Inglés | MEDLINE | ID: mdl-32972970

RESUMEN

OBJECTIVE: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety. METHODS: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions. RESULTS: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup (p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning (r = -0.950, p = 0.001) and memory (r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex. CONCLUSIONS: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations.


Asunto(s)
Ansiedad , Disfunción Cognitiva , Depresión , Fatiga , Esclerosis Múltiple , Proteínas de Neurofilamentos/sangre , Adolescente , Adulto , Ansiedad/sangre , Ansiedad/etiología , Ansiedad/fisiopatología , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Depresión/sangre , Depresión/etiología , Depresión/fisiopatología , Fatiga/sangre , Fatiga/etiología , Fatiga/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Medición de Resultados Informados por el Paciente , Índice de Severidad de la Enfermedad , Adulto Joven
5.
Brain ; 143(4): 1127-1142, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32293668

RESUMEN

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.


Asunto(s)
4-Aminopiridina/farmacología , Esclerosis Múltiple/patología , Fármacos Neuroprotectores/farmacología , Neuritis Óptica/patología , Degeneración Retiniana/patología , Adulto , Anciano , Animales , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Células-Madre Neurales/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar
6.
Acta Neurol Scand ; 140(4): 290-295, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31269227

RESUMEN

OBJECTIVES: To identify possible risk factors influencing the incidence of intravenous immunoglobulin (IVIg) treatment-related cephalalgia in neurological diseases. MATERIALS & METHODS: Retrospective chart review of neurological patients receiving IVIg treatment between July 13, 2017, and August 14, 2017. Patients with MS receiving natalizumab in the same setting were observed as a reference group. RESULTS: Patients with headache after IVIg infusion (n = 22 infusions) showed a reduced heart rate (by 6.0 ± 8.5 beats per minute [bpm]), but no significant difference in blood pressure. Patients without headache after IVIg infusion (n = 69 infusions) showed a higher systolic blood pressure increase and a stronger reduction in the heart rate (by 5.7 ± 8.6 bpm), compared to patients with headache after IVIg infusion. The infusion rate was significantly slower and age significantly lower in patients developing headache after IVIg infusion. Body temperature was unchanged in both groups. Binary logistic regression analysis revealed that blood pressure at baseline and age significantly influence the occurrence of cephalalgia. In reference, patients receiving natalizumab (ie, shorter infusions/smaller infusion volume), systolic blood pressure, and heart rate decreased, while body temperature increased. Here, one patient developed headache. CONCLUSIONS: Intravenous immunoglobulin-associated headache is not associated with an increased blood pressure after infusion but with a reduced heart rate, a slower infusion rate, female sex and seems to be influenced by baseline systolic blood pressure and age. A reaction to immunoglobulin aggregates, stabilizers, or vasoactive mediators are possible explanations. The absence of an association with body temperature does not suggest a systemic immune response as a cause for headache.


Asunto(s)
Cefalea/inducido químicamente , Cefalea/fisiopatología , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/fisiopatología , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Femenino , Cefalea/diagnóstico , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Infusiones Intravenosas/efectos adversos , Infusiones Intravenosas/métodos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Resultado del Tratamiento
7.
Acta Neuropathol ; 137(2): 239-257, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30426203

RESUMEN

Brain accumulation and aggregation of amyloid-ß (Aß) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aß peptides (mainly Aß1-40 and Aß1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by ß- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aß peptides are truncated at the N-terminus, with Aß4-x peptides being particularly abundant. Aß4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aß peptide sequence, which facilitates Aß4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aß4-40 but unchanged levels of Aß1-x peptides. In the 5xFAD mouse model of amyloidosis, Aß4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4-/- knockout background, Aß4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aß species, but Aß4-40 peptides were absent in cultures derived from ADAMTS4-/- mice indicating that the enzyme was essential for Aß4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aß4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aß peptides.


Asunto(s)
Proteína ADAMTS4/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Oligodendroglía/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Ratones , Oligodendroglía/patología , Fragmentos de Péptidos/metabolismo , Placa Amiloide/patología
8.
Mult Scler ; 24(13): 1776-1778, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30307371

RESUMEN

BACKGROUND: Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial. OBJECTIVE: To report a case of acute sarcoidosis (Löfgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment. CASE REPORT: Sarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased). CONCLUSION: Our case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications.


Asunto(s)
Alemtuzumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Sarcoidosis/tratamiento farmacológico , Adulto , Antígenos CD19/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Humanos , Recuento de Linfocitos
9.
Glia ; 65(9): 1521-1534, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28618115

RESUMEN

Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl-diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Glutarredoxinas/metabolismo , Microglía/metabolismo , Óxido Nítrico/metabolismo , Oligodendroglía/metabolismo , Animales , Cerebelo/metabolismo , Cerebelo/patología , Encefalomielitis Autoinmune Experimental/patología , Escherichia coli , Femenino , Glutarredoxinas/genética , Glutatión Transferasa/metabolismo , Células HeLa , Humanos , Inflamación/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL , Microglía/patología , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuroprotección/fisiología , Oligodendroglía/patología , Ácido Peroxinitroso/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Schistosoma japonicum , Técnicas de Cultivo de Tejidos
11.
Biochim Biophys Acta ; 1850(8): 1575-87, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25450486

RESUMEN

BACKGROUND: The cytoskeleton, unlike the bony vertebrate skeleton or the exoskeleton of invertebrates, is a highly dynamic meshwork of protein filaments that spans through the cytosol of eukaryotic cells. Especially actin filaments and microtubuli do not only provide structure and points of attachments, but they also shape cells, they are the basis for intracellular transport and distribution, all types of cell movement, and--through specific junctions and points of adhesion--join cells together to form tissues, organs, and organisms. SCOPE OF REVIEW: The fine tuned regulation of cytoskeletal dynamics is thus indispensible for cell differentiation and all developmental processes. Here, we discussed redox signalling mechanisms that control this dynamic remodeling. Foremost, we emphasised recent discoveries that demonstrated reversible thiol and methionyl switches in the regulation of actin dynamics. MAJOR CONCLUSIONS: Thiol and methionyl switches play an essential role in the regulation of cytoskeletal dynamics. GENERAL SIGNIFICANCE: The dynamic remodeling of the cytoskeleton is controlled by various redox switches. These mechanisms are indispensible during development and organogenesis and might contribute to numerous pathological conditions. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.


Asunto(s)
Desdiferenciación Celular/fisiología , Diferenciación Celular/fisiología , Proteínas del Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Animales , Humanos , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/fisiopatología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Oxidación-Reducción
12.
Proc Natl Acad Sci U S A ; 110(50): 20057-62, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24277839

RESUMEN

Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified for glutaredoxin 2, a vertebrate-specific glutathione-disulfide oxidoreductase with a critical role for embryonic brain development. Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD(+)-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.


Asunto(s)
Sistema Cardiovascular/embriología , Glutarredoxinas/metabolismo , Glutatión/metabolismo , Neovascularización Fisiológica/fisiología , Transducción de Señal/fisiología , Sirtuina 1/metabolismo , Animales , Western Blotting , Cartilla de ADN/genética , Técnicas de Silenciamiento del Gen , Glutarredoxinas/genética , Células HeLa , Humanos , Espectrometría de Masas , Microscopía Confocal , Oxidación-Reducción , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Imagen de Lapso de Tiempo , Pez Cebra
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