RESUMEN
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting predominantly adults. It is a complex disease associated with both environmental and genetic risk factors. Although over 230 risk single-nucleotide polymorphisms have been associated with MS, all are common human variants. The mechanisms by which they increase the risk of MS, however, remain elusive. We hypothesized that a complex genetic phenotype such as MS could be driven by coordinated expression of genes controlled by transcriptional regulatory networks. We, therefore, constructed a gene coexpression network from microarray expression analyses of five purified peripheral blood leukocyte subsets of 76 patients with relapsing remitting MS and 104 healthy controls. These analyses identified a major network (or module) of expressed genes associated with MS that play key roles in cell-mediated cytotoxicity which was downregulated in monocytes of patients with MS. Manipulation of the module gene expression was achieved in vitro through small interfering RNA gene knockdown of identified drivers. In a mouse model, network gene knockdown modulated the autoimmune inflammatory MS model disease-experimental autoimmune encephalomyelitis. This research implicates a cytotoxicity-associated gene network in myeloid cells in the pathogenesis of MS.
RESUMEN
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
Asunto(s)
Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Regulación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Monocitos/metabolismo , Esclerosis Múltiple/metabolismo , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Factores de Riesgo , Tirosina Quinasa c-MerRESUMEN
In order to further investigate the molecular mechanisms that regulate oligodendrocyte (OC) survival, we utilized microarrays to characterize changes in OC gene expression after exposure to the cytokines neurotrophin3, insulin, or leukemia inhibitory factor (LIF) in vitro. We identified and validated the induction and secretion of the neuropeptide galanin in OCs, specifically in response to LIF. We next established that galanin is an OC survival factor and showed that autocrine or paracrine galanin secretion mediates LIF-induced OC survival in vitro. We also revealed that galanin is up-regulated in OCs in the cuprizone model of central demyelination, and that oligodendroglial galanin expression is significantly regulated by endogenous LIF in this context. We also showed that knock-out of galanin reduces OC survival and exacerbates callosal demyelination in the cuprizone model. These findings suggest a potential role for the use of galanin agonists in the treatment of human demyelinating diseases.
Asunto(s)
Galanina/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Vaina de Mielina/fisiología , Oligodendroglía/fisiología , Animales , Astrocitos/patología , Astrocitos/fisiología , Encéfalo/patología , Encéfalo/fisiopatología , Supervivencia Celular/fisiología , Células Cultivadas , Cuprizona , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/fisiopatología , Modelos Animales de Enfermedad , Galanina/genética , Expresión Génica , Sistema de Señalización de MAP Quinasas/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Vaina de Mielina/patología , Células-Madre Neurales/patología , Células-Madre Neurales/fisiología , Oligodendroglía/patología , Nervio Óptico/patología , Nervio Óptico/fisiología , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.
Asunto(s)
Ceruloplasmina/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Animales , Western Blotting , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/patología , TranscriptomaRESUMEN
At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
Asunto(s)
Inmunidad Adaptativa , Predisposición Genética a la Enfermedad , Variación Genética , Inmunidad Innata , Esclerosis Múltiple/etiología , Inmunidad Adaptativa/genética , Alelos , Estudios de Casos y Controles , Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Inmunidad Innata/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Carácter Cuantitativo Heredable , Medición de Riesgo , Factores de RiesgoRESUMEN
The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl, Mer, and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 +/- 3.1 vs 11.8 +/- 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor alpha mRNA expression was reduced approximately 48%). In Gas6-/- mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-pi (glutathione S-transferase-pi)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6-/- mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6-/- mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.
Asunto(s)
Enfermedades Desmielinizantes/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Microglía/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Oligodendroglía/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Muerte Celular/genética , Supervivencia Celular/genética , Células Cultivadas , Quelantes , Técnicas de Cocultivo , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/fisiopatología , Modelos Animales de Enfermedad , Gliosis/genética , Gliosis/metabolismo , Gliosis/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibras Nerviosas Mielínicas/patología , Neurotoxinas , Oligodendroglía/patología , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Ratas Sprague-Dawley , Tirosina Quinasa c-Mer , Tirosina Quinasa del Receptor AxlRESUMEN
In multiple sclerosis, inflammatory axonal injury is a key pathological mechanism responsible for the development of progressive neurological dysfunction. The injured axon represents a therapeutic target in this disease; however, therapeutic trials of neuroprotective candidates will initially require preclinical testing in an animal model of inflammatory axonal injury and subsequently the development of a reliable paraclinical measure of axonal degeneration in humans. In the present study, we demonstrate the validity of serum phosphorylated neurofilament H (pNF-H) as a marker of axonal injury in murine experimental autoimmune encephalomyelitis (EAE). At the time of maximum disease severity (EAE day 22), the average serum pNF-H level reached 5.7 ng/ml, correlating significantly with the EAE paraplegia score (r = 0.75, P < 0.001). On average, 40% of axons in the spinal cord were lost in EAE, and serum pNF-H levels were highly correlated with axon loss (r = 0.8, P < 0.001). Axonal injury was a severe and acute event, insofar as serum pNF-H levels were not significantly elevated at early (EAE day 12) or late (EAE days 35 and 50) disease time points. Our results demonstrate that acute inflammatory axonal injury is a pathological feature of murine MOG(35-55) EAE, indicating that this model may mirror the acute pathological events in active multiple sclerosis lesions. Furthermore, we have validated the serum pNF-H assay as an unbiased measurement of axonal injury in EAE, facilitating rapid screening of potential neuroprotective therapies in this model.
Asunto(s)
Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/diagnóstico , Proteínas de Neurofilamentos/sangre , Médula Espinal/metabolismo , Degeneración Walleriana/sangre , Degeneración Walleriana/diagnóstico , Enfermedad Aguda , Animales , Axones/metabolismo , Axones/patología , Biomarcadores/análisis , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/fisiopatología , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/patología , Proteínas de Neurofilamentos/análisis , Fosforilación , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Médula Espinal/patología , Médula Espinal/fisiopatología , Degeneración Walleriana/fisiopatologíaRESUMEN
Injury to axons and oligodendrocytes has been poorly characterized in most animal models of stroke, and hence has been difficult to target therapeutically. It is therefore necessary to characterize axonal and oligodendroglial injury in these models, in order to rationally design putative protective compounds that minimize this injury. This study aims to characterize injury to axons and oligodendrocytes in the endothelin-1 (ET-1) model of middle cerebral artery occlusion (MCAO) in conscious rats. Transient forebrain ischemia was induced in conscious adult male Long Evans rats by the perivascular microinjection of ET-1. Quantitative histopathology was performed on forebrain sections at 6, 24, 48 and 72 h after ET-1 administration, using ballistic light analyses and immunohistochemistry for amyloid precursor protein (APP), SMI32, and Tau-1. Ballistic light analyses of cortical and striatal lesions revealed that the infarct volume was maximal in these regions by 6 h. APP and SMI32 immunohistochemistry demonstrated that axonal injury was maximal by 6 h in this model; however, some injured axons appeared to maintain good structural integrity up to 72 h after insult. Density measurements for Tau-1-immunopositive oligodendrocytes were significantly elevated within the corpus callosum from 48 h, but reductions in total oligodendrocyte numbers were not apparent up 72 h after ET-1 injection. These results indicate that axonal and oligodendroglial injury should be investigated as potential targets for delayed therapeutic intervention after MCAO.
Asunto(s)
Lesión Axonal Difusa/patología , Endotelina-1 , Infarto de la Arteria Cerebral Media/inducido químicamente , Oligodendroglía/patología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Recuento de Células/métodos , Lesión Axonal Difusa/etiología , Modelos Animales de Enfermedad , Inmunohistoquímica/métodos , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Proteínas de Neurofilamentos/metabolismo , Ratas , Ratas Long-Evans , Factores de TiempoRESUMEN
BACKGROUND: Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. OBJECTIVE: In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. METHODS: The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. RESULTS: In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. CONCLUSION: These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.
RESUMEN
BACKGROUND: The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) play important roles in modulating innate immune responses and central demyelination. The TAM receptor ligand Protein S (PROS) has also been shown to modulate innate immune cell responses. OBJECTIVES: We assessed whether plasma levels of PROS are changed in multiple sclerosis (MS) patients and whether changes are associated with disease severity. METHODS: Plasma levels of total and free PROS were measured using enzyme-linked immunosorbent assay in a discovery cohort (MS: 65, control: 14) and an independent replication cohort (MS: 29, control: 29). The Multiple Sclerosis Severity Score (MSSS) was used to evaluate associations between plasma PROS levels and disease severity. RESULTS: We found plasma levels of total, but not free PROS, were decreased in MS patients compared with controls. In female MS patients, we observed decreases in total and free PROS levels compared with controls. In addition, we also observed higher MSSS in patients with very low levels of plasma free PROS. CONCLUSIONS: These data suggest PROS may represent a potential marker of disease severity in MS.
RESUMEN
BACKGROUND: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system. RESULTS: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury. CONCLUSIONS: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Médula Espinal/inmunología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Animales , Proteínas Reguladoras de la Apoptosis , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Interleucina-1beta/metabolismo , Macrófagos/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/inmunología , Esclerosis Múltiple/metabolismo , Neuroinmunomodulación/fisiología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Índice de Severidad de la Enfermedad , Linfocitos T/fisiologíaRESUMEN
The EphA4 receptor tyrosine kinase is a major regulator of axonal growth and astrocyte reactivity and is a possible inflammatory mediator. Given that multiple sclerosis (MS) is primarily an inflammatory demyelinating disease and in mouse models of MS, such as experimental autoimmune encephalomyelitis (EAE), axonal degeneration and reactive gliosis are prominent clinical features, we hypothesised that endogenous EphA4 could play a role in modulating EAE. EAE was induced in EphA4 knockout and wildtype mice using MOG peptide immunisation and clinical severity and histological features of the disease were then compared in lumbar spinal cord sections. EphA4 knockout mice exhibited a markedly less severe clinical course than wildtype mice, with a lower maximum disease grade and a slightly later onset of clinical symptoms. Numbers of infiltrating T cells and macrophages, the number and size of the lesions, and the extent of astrocytic gliosis were similar in both genotypes; however, EphA4 knockout mice appeared to have decreased axonal pathology. Blocking of EphA4 in wildtype mice by administration of soluble EphA4 (EphA4-Fc) as a decoy receptor following induction of EAE produced a delay in onset of clinical symptoms; however, most mice had clinical symptoms of similar severity by 22 days, indicating that EphA4 blocking treatment slowed early EAE disease evolution. Again there were no apparent differences in histopathology. To determine whether the role of EphA4 in modulating EAE was CNS mediated or due to an altered immune response, MOG primed T cells from wildtype and EphA4 knockout mice were passively transferred into naive recipient mice and both were shown to induce disease of equivalent severity. These results are consistent with a non-inflammatory, CNS specific, deleterious effect of EphA4 during neuroinflammation that results in axonal pathology.
Asunto(s)
Astrocitos/inmunología , Axones/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Receptor EphA4/genética , Médula Espinal/inmunología , Traslado Adoptivo , Animales , Astrocitos/patología , Axones/patología , Movimiento Celular , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Femenino , Eliminación de Gen , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/farmacología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/inmunología , Glicoproteína Mielina-Oligodendrócito/farmacología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Receptor EphA4/antagonistas & inhibidores , Receptor EphA4/inmunología , Índice de Severidad de la Enfermedad , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Linfocitos T/trasplanteRESUMEN
Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG35â55 EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1±0.14 vs 2.6±0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540±207 µm²-/s vs 1310±175 µm²-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism.
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Factor Neurotrófico Ciliar/genética , Encefalomielitis Autoinmune Experimental/genética , Factor Inhibidor de Leucemia/genética , Animales , Axones/metabolismo , Factor Neurotrófico Ciliar/metabolismo , Receptor gp130 de Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Factor Inhibidor de Leucemia/metabolismo , Ratones , Ratones Noqueados , Oligodendroglía/metabolismo , Transducción de SeñalRESUMEN
Biomarkers of axonal degeneration have the potential to improve our capacity to predict and monitor neurological outcome in multiple sclerosis (MS) patients. Neurofilament proteins, one of the major proteins expressed within neurons and axons, have been detected in cerebrospinal fluid and blood samples from MS patients and are now being actively investigated for their utility as prognostic indicators of disease progression in MS. In this paper, we summarize the current literature on neurofilament structure, assembly, and degeneration and discuss their potential utility as biomarkers for monitoring neurological decline in MS. We also discuss the need to further develop sensitive methods for assaying neurofilaments in blood to improve clinical applicability.