ABSTRACT
Gelsolin is the fourth most abundant protein in the body and its depletion in the blood has been found in multiple sclerosis (MS) patients. How gelsolin affects the MS brain has not been studied. We found that while the secreted form of gelsolin (pGSN) decreased in the blood of experimental autoimmune encephalomyelitis (EAE) mice, pGSN concentration increased in the EAE brain. Recombinant human pGSN (rhp-GSN) decreased extracellular actin and myeloperoxidase activity in the brain, resulting in reduced disease activity and less severe clinical disease, suggesting that gelsolin could be a potential therapeutic target for MS.
Subject(s)
Actins/toxicity , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gelsolin/metabolism , Gelsolin/therapeutic use , Multiple Sclerosis/drug therapy , Actins/metabolism , Animals , Brain/drug effects , Brain/metabolism , CD11b Antigen/metabolism , Cell Line, Tumor , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Freund's Adjuvant/toxicity , Glioma/pathology , Humans , Mice , Multiple Sclerosis/etiology , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Mycobacterium tuberculosis/immunology , Myelin Proteolipid Protein/toxicity , Neutrophils/drug effects , Neutrophils/metabolism , Peptide Fragments/toxicity , Peroxidase/metabolism , Time FactorsABSTRACT
Representing the most common cause of dementia, Alzheimer's disease (AD) has dramatically impacted the neurological and economic health of our society. AD is a debilitating neurodegenerative disease that produces marked cognitive decline. Much evidence has accumulated over the past decade to suggest soluble oligomers of beta-amyloid (Aß) have a critical role in mediating AD pathology early in the disease process by perturbing synaptic efficacy. Here we critically review recent research that implicates synapses as key sites of early pathogenesis in AD. Most excitatory synapses in the brain rely on dendritic spines as the sites for excitatory neurotransmission. The structure and function of dendritic spines are dynamically regulated by cellular pathways acting on the actin cytoskeleton. Numerous studies analyzing human postmortem tissue, animal models and cellular paradigms indicate that AD pathology has a deleterious effect on the pathways governing actin cytoskeleton stability. Based on the available evidence, we propose the idea that a contributing factor to synaptic pathology in early AD is an Aß oligomer-initiated collapse of a "synaptic safety net" in spines, leading to dendritic spine degeneration and synaptic dysfunction. Spine stabilizing pathways may thus represent efficacious therapeutic targets for combating AD pathology.
Subject(s)
Actin Cytoskeleton/pathology , Actins/toxicity , Alzheimer Disease/pathology , Synapses/pathology , Actin Cytoskeleton/chemistry , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Animals , Dendritic Spines/pathology , Humans , Synapses/chemistry , Synapses/physiology , Synaptic Transmission/physiologyABSTRACT
Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.
Subject(s)
Catechol O-Methyltransferase/biosynthesis , Catechols/toxicity , Environmental Pollutants/toxicity , Estrogens, Non-Steroidal , Neoplasms/chemically induced , Phenols/toxicity , Polychlorinated Biphenyls/toxicity , Receptors, Estrogen/drug effects , Actins/toxicity , Blotting, Western , Catechols/metabolism , Catechols/pharmacology , Cell Line, Tumor , Electrophoresis, Polyacrylamide Gel , Environmental Pollutants/metabolism , Environmental Pollutants/pharmacology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Fulvestrant , Humans , Neoplasms/epidemiology , Phenols/metabolism , Phenols/pharmacology , Polychlorinated Biphenyls/metabolism , Polychlorinated Biphenyls/pharmacology , RiskABSTRACT
Actin released from damaged cells after a variety of tissue injuries appears to be involved in multiple organ dysfunction syndrome. Under experimental conditions, when the quantity of actin present in plasma is made to exceed the protective capacity of the actin-scavenging mechanism, microembolism and pulmonary vascular angiopathy have been noted in rats. It remains to be determined whether this injury is a result of a direct toxic effect or occurs indirectly via platelet activation or fibrin interactions. We examined the effect of sera from patients with adult respiratory distress syndrome (ARDS), as well as G-actin added to normal serum, on the viability, morphology, and function of cultured sheep pulmonary artery endothelial cells (SPAEC). Both patient sera and normal sera to which actin was added were toxic in the cell culture model; this toxicity could be abrogated, at least partially, by preincubation with gelsolin, which is known to complex with actin. A significant portion of the toxicity of sera from patients with ARDS was sensitive to heat (56 degrees C), suggesting an important role of complement. Sera from patients with ARDS were shown to contain filaments of F-actin by immunoblot and rhodamine phalloidin staining after ultracentrifugation. Thus, saturation of the actin-scavenging system by addition of exogenous G-actin to plasma produces direct pulmonary endothelial cell injury. Furthermore, plasma from patients with ARDS secondary to bacterial pneumonia is toxic to SPAEC, and a small but significant contributory role of actin is apparent in these studies.
Subject(s)
Actins/blood , Actins/toxicity , Endothelium, Vascular/cytology , Pulmonary Artery/cytology , Respiratory Distress Syndrome/blood , Animals , Cells, Cultured , Humans , SheepABSTRACT
The ADP-ribosylating toxins Clostridium botulinum C2 toxin and C. perfringens iota toxin, which ADP-ribosylate monomeric G-actin at Arg-177 but not the polymeric F-actin, induce depolymerization of the actin cytoskeleton in cultured cells. Since ADP-ribosylated G-actin has properties of a barbed-end-capping protein, we studied whether the ADP-ribosylated actin affects the actin cytoskeleton of PtK2 cells even in the absence of ADP-ribosylating toxin. Skeletal muscle actin was ADP-ribosylated by C. perfringens iota toxin and the toxin was removed using an anti-iota toxin antibody. Microinjection of ADP-ribosylated actin caused retraction of the cell body, redistribution and depolymerization of the actin cytoskeleton in a concentration- and time-dependent manner. The finding that ADP-ribosylated actin affects per se the actin cytoskeleton explains the cytopathic effects of ADP-ribosylating toxins on microfilaments, although F-actin is not directly modified by the toxins.
