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1.
J Biol Chem ; 300(6): 107313, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38657864

RESUMEN

Sortilin-related receptor 1 (SORL1) is an intracellular sorting receptor genetically implicated in Alzheimer's disease (AD) that impacts amyloid precursor protein trafficking. The objective of these studies was to test the hypothesis that SORL1 binds tau, modulates its cellular trafficking and impacts the aggregation of cytoplasmic tau induced by pathological forms of tau. Using surface plasmon resonance measurements, we observed high-affinity binding of tau to SORL1 and the vacuolar protein sorting 10 domain of SORL1. Interestingly, unlike LDL receptor-related protein 1, SORL1 binds tau at both pH 7.4 and pH 5.5, revealing its ability to bind tau at endosomal pH. Immunofluorescence studies confirmed that exogenously added tau colocalized with SORL1 in H4 neuroglioma cells, while overexpression of SORL1 in LDL receptor-related protein 1-deficient Chinese hamster ovary (CHO) cells resulted in a marked increase in the internalization of tau, indicating that SORL1 can bind and mediate the internalization of monomeric forms of tau. We further demonstrated that SORL1 mediates tau seeding when tau RD P301S FRET biosensor cells expressing SORL1 were incubated with high molecular weight forms of tau isolated from the brains of patients with AD. Seeding in H4 neuroglioma cells is significantly reduced when SORL1 is knocked down with siRNA. Finally, we demonstrate that the N1358S mutant of SORL1 significantly increases tau seeding when compared to WT SORL1, identifying for the first time a potential mechanism that connects this specific SORL1 mutation to Alzheimer's disease. Together, these studies identify SORL1 as a receptor that contributes to trafficking and seeding of pathogenic tau.

2.
Proc Natl Acad Sci U S A ; 121(17): e2314450121, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38621133

RESUMEN

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (Aß) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, clears Aß plaque from the brain and slows cognitive decline. Here, we show that lecanemab blocks fibrinogen's binding to Aß protofibrils, preventing Aß/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aß/fibrinogen complex and prevents fibrinogen from exacerbating Aß-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.


Asunto(s)
Enfermedad de Alzheimer , Anticuerpos Monoclonales Humanizados , Trombosis , Ratones , Humanos , Animales , Fibrinógeno/metabolismo , Sistemas Microfisiológicos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo
3.
bioRxiv ; 2024 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-38293058

RESUMEN

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (Aß) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, shows promising results in facilitating reduction of Aß from the brain and slowing cognitive decline. Here we show that lecanemab blocks fibrinogen's binding to Aß protofibrils, normalizing Aß/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aß/fibrinogen complex and prevents fibrinogen from exacerbating Aß-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.

4.
Int J Mol Sci ; 24(8)2023 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-37108211

RESUMEN

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aß) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the vasculature, a decrease in cerebral blood flow, and accumulation of Aß along vessels, among others. Vascular dysfunction begins early in disease pathogenesis and may contribute to disease progression and cognitive dysfunction. In addition, patients with AD exhibit alterations in the plasma contact system and the fibrinolytic system, two pathways in the blood that regulate clotting and inflammation. Here, we explain the clinical manifestations of vascular deficits in AD. Further, we describe how changes in plasma contact activation and the fibrinolytic system may contribute to vascular dysfunction, inflammation, coagulation, and cognitive impairment in AD. Given this evidence, we propose novel therapies that may, alone or in combination, ameliorate AD progression in patients.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Péptidos beta-Amiloides/metabolismo , Ovillos Neurofibrilares/metabolismo , Inflamación/metabolismo
5.
J Neuroinflammation ; 20(1): 56, 2023 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-36864439

RESUMEN

BACKGROUND: Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson's disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored. In PD models and in human patients, ß-adrenergic receptors' (AR) signaling is associated with a reduction of neuroinflammation and PD pathology. However, the effect of NE depletion in the brain and the extent of NE and ß-ARs signaling involvement in neuroinflammation, and dopaminergic neuron survival is poorly understood. METHODS: Two mouse models of PD, a 6OHDA neurotoxin-based model and a human α-synuclein (hα-SYN) virus-based model of PD, were used. DSP-4 was used to deplete NE levels in the brain and its effect was confirmed by HPLC with electrochemical detection. A pharmacological approach was used to mechanistically understand the impact of DSP-4 in the hα-SYN model of PD using a norepinephrine transporter (NET) and a ß-AR blocker. Epifluorescence and confocal imaging were used to study changes in microglia activation and T-cell infiltration after ß1-AR and ß2-AR agonist treatment in the hα-SYN virus-based model of PD. RESULTS: Consistent with previous studies, we found that DSP-4 pretreatment increased dopaminergic neuron loss after 6OHDA injection. In contrast, DSP-4 pretreatment protected dopaminergic neurons after hα-SYN overexpression. DSP-4-mediated protection of dopaminergic neurons after hα-SYN overexpression was dependent on ß-AR signaling since using a ß-AR blocker prevented DSP-4-mediated dopaminergic neuron protection in this model of PD. Finally, we found that the ß-2AR agonist, clenbuterol, reduced microglia activation, T-cell infiltration, and dopaminergic neuron degeneration, whereas xamoterol a ß-1AR agonist showed increased neuroinflammation, blood brain barrier permeability (BBB), and dopaminergic neuron degeneration in the context of hα-SYN-mediated neurotoxicity. CONCLUSIONS: Our data demonstrate that the effects of DSP-4 on dopaminergic neuron degeneration are model specific, and suggest that in the context of α-SYN-driven neuropathology, ß2-AR specific agonists may have therapeutic benefit in PD.


Asunto(s)
Síndromes de Neurotoxicidad , Enfermedad de Parkinson , Animales , Humanos , Ratones , alfa-Sinucleína , Neuronas Dopaminérgicas , Degeneración Nerviosa , Enfermedades Neuroinflamatorias , Neurotoxinas , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo
7.
Blood ; 140(4): 388-400, 2022 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-35576527

RESUMEN

The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly improve neurologic outcomes; however, thrombolytic therapy is associated with an increased risk of intracerebral hemorrhage (ICH). The risk of hemorrhage significantly limits the use of thrombolytic therapy, and identifying pathways induced by tPA that increase this risk could provide new therapeutic options to extend thrombolytic therapy to a wider patient population. Here, we investigate the role of protein kinase Cß (PKCß) phosphorylation of the tight junction protein occludin during ischemic stroke and its role in cerebrovascular permeability. We show that activation of this pathway by tPA is associated with an increased risk of ICH. Middle cerebral artery occlusion (MCAO) increased phosphorylation of occludin serine 490 (S490) in the ischemic penumbra in a tPA-dependent manner, as tPA-/- mice were significantly protected from MCAO-induced occludin phosphorylation. Intraventricular injection of tPA in the absence of ischemia was sufficient to induce occludin phosphorylation and vascular permeability in a PKCß-dependent manner. Blocking occludin phosphorylation, either by targeted expression of a non-phosphorylatable form of occludin (S490A) or by pharmacologic inhibition of PKCß, reduced MCAO-induced permeability and improved functional outcome. Furthermore, inhibiting PKCß after MCAO prevented ICH associated with delayed thrombolysis. These results show that PKCß phosphorylation of occludin is a downstream mediator of tPA-induced cerebrovascular permeability and suggest that PKCß inhibitors could improve stroke outcome and prevent ICH associated with delayed thrombolysis, potentially extending the window for thrombolytic therapy in stroke.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/etiología , Fibrinolíticos/uso terapéutico , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ratones , Ocludina/genética , Ocludina/metabolismo , Fosforilación , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiología , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/metabolismo
8.
Transl Stroke Res ; 13(5): 801-815, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35122213

RESUMEN

Tissue plasminogen activator (tPA) is a multifunctional protease. In blood tPA is best understood for its role in fibrinolysis, whereas in the brain tPA is reported to regulate blood-brain barrier (BBB) function and to promote neurodegeneration. Thrombolytic tPA is used for the treatment of ischemic stroke. However, its use is associated with an increased risk of hemorrhagic transformation. In blood the primary regulator of tPA activity is plasminogen activator inhibitor 1 (PAI-1), whereas in the brain, its primary inhibitor is thought to be neuroserpin (Nsp). In this study, we compare the effects of PAI-1 and Nsp deficiency in a mouse model of ischemic stroke and show that tPA has both beneficial and harmful effects that are differentially regulated by PAI-1 and Nsp. Following ischemic stroke Nsp deficiency in mice leads to larger strokes, increased BBB permeability, and increased spontaneous intracerebral hemorrhage. In contrast, PAI-1 deficiency results in smaller infarcts and increased cerebral blood flow recovery. Mechanistically, our data suggests that these differences are largely due to the compartmentalized action of PAI-1 and Nsp, with Nsp deficiency enhancing tPA activity in the CNS which increases BBB permeability and worsens stroke outcomes, while PAI-1 deficiency enhances fibrinolysis and improves recovery. Finally, we show that treatment with a combination therapy that enhances endogenous fibrinolysis by inhibiting PAI-1 with MDI-2268 and reduces BBB permeability by inhibiting tPA-mediated PDGFRα signaling with imatinib significantly reduces infarct size compared to vehicle-treated mice and to mice with either treatment alone.


Asunto(s)
Hemorragia Cerebral , Accidente Cerebrovascular Isquémico , Neuropéptidos , Inhibidor 1 de Activador Plasminogénico , Serpinas , Animales , Barrera Hematoencefálica , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Trastornos Hemorrágicos , Ratones , Neuropéptidos/metabolismo , Inhibidor 1 de Activador Plasminogénico/deficiencia , Inhibidor 1 de Activador Plasminogénico/metabolismo , Serpinas/metabolismo , Activador de Tejido Plasminógeno/efectos adversos , Neuroserpina
9.
Front Biosci (Elite Ed) ; 7(3): 434-46, 2015 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-25961423

RESUMEN

Platelet-derived growth factor receptor alpha (PDGFRalpha) interacts with PDGFs A, B, C and AB, while PDGFRbeta binds to PDGFs B and D, thus suggesting that PDGFRalpha is more promiscuous than PDGFRbeta. The structural analysis of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes and a molecular explanation for the promiscuity of PDGFRalpha and the specificity of PDGFRbeta remain unclear. In the present study, we modeled the three extracellular domains of PDGFRalpha using a previous crystallographic structure of PDGFRbeta as a template. Additionally, we analyzed the interacting residues of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes using docking simulations. The validation of the resulting complexes was evaluated by molecular dynamics simulations. Structural analysis revealed that changes of non-aromatic amino acids in PDGFRalpha to aromatic amino acids in PDGFRbeta (I139F, P267F and N204Y) may be involved in the promiscuity of PDGFRalpha. Indeed, substitution of amino acids with few probabilities of rotamer changes in PDGFRbeta (M133A, N163E and N179S) and energy stability due to the formation of hydrogen bond in PDGFRbeta could explain the specificity of PDGFRbeta. These results may be used as an input for a better and more specific drug and peptide design targeting diseases related with the malfunction of PDGFs and PDGFRalpha such as cancer and atherosclerosis.


Asunto(s)
Receptor beta de Factor de Crecimiento Derivado de Plaquetas/química , Sitios de Unión , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Alineación de Secuencia , Análisis de Secuencia de Proteína , Transducción de Señal
10.
Langmuir ; 31(11): 3527-36, 2015 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-25742562

RESUMEN

Gold nanoparticles with anisotropic structures have tunable absorption properties and diverse bioapplications as image contrast agents, plasmonics, and therapeutic-diagnostic materials. Amino acids with electrostatically charged side chains possess inner affinity for metal ions. Lysine (Lys) efficiently controlled the growing into star-shape nanoparticles with controlled narrow sizes (30-100 nm) and produced in high yields (85-95%). Anisotropic nanostructures showed tunable absorbance from UV to NIR range, with extraordinary colloidal stability (-26 to -42 mV) and surface-enhanced Raman scattering properties. Advanced electron microscopy characterization through ultra-high-resolution SEM, STEM, and HR-TEM confirmed the size, nanostructure, crystalline structure, and chemical composition. Molecular dynamics simulations revealed that Lys interacted preferentially with Au(I) through the -COOH group instead of their positive side chains with a binding free energy (BFE) of 3.4 kcal mol(-1). These highly monodisperse and colloidal stable anisotropic particles prepared with biocompatible compounds may be employed in biomedical applications.


Asunto(s)
Oro/química , Nanopartículas del Metal/química , Anisotropía , Coloides/química
11.
Langmuir ; 31(8): 2455-62, 2015 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-25658387

RESUMEN

The adsorption behavior of hard and soft proteins under the effect of an external electric field was investigated by a combination of spectroscopic ellipsometry and molecular dynamics (MD) simulations. Optically transparent carbon electrodes (OTCE) were used as conductive, sorbent substrates. Lysozyme (LSZ) and ribonuclease A (RNase A) were selected as representative hard proteins, whereas myoglobin (Mb), α-lactalbumin (α-LAC), bovine serum albumin (BSA), glucose oxidase (GOx), and immunoglobulin G (IgG) were selected to represent soft proteins. In line with recent publications from our group, the experimental results revealed that while the adsorption of all investigated proteins can be enhanced by the potential applied to the electrode, the effect is more pronounced for hard proteins. In contrast with the incomplete monolayers formed at open-circuit potential, the application of +800 mV to the sorbent surface induced the formation of multiple layers of protein. These results suggest that this effect can be related to the intrinsic polarizability of the protein (induction of dipoles), the resulting surface accessible solvent area (SASA), and structural rearrangements induced upon the incorporation on the protein layer. The described experiments are critical to understand the relationship between the structure of proteins and their tendency to form (under electric stimulation) layers with thicknesses that greatly surpass those obtained at open-circuit conditions.


Asunto(s)
Carbono/química , Muramidasa/química , Ribonucleasa Pancreática/química , Adsorción , Animales , Bovinos , Electricidad , Electrodos , Modelos Moleculares , Muramidasa/metabolismo , Tamaño de la Partícula , Ribonucleasa Pancreática/metabolismo , Propiedades de Superficie
12.
J Colloid Interface Sci ; 435: 164-70, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25261840

RESUMEN

This article describes the adsorption of glucose oxidase (GOx) onto optically transparent carbon electrodes (OTCE) under the effect of applied potential and the analysis of the enzymatic activity of the resulting GOx/OTCE substrates. In order to avoid electrochemical interferences with the enzyme redox center, control electrochemical experiments were performed using flavin adenine dinucleotide (FAD) and GOx/OTCE substrates. Then, the enzyme adsorption experiments were carried out as a function of the potential applied (ranged from the open circuit potential to +950mV), the pH solution, the concentration of enzyme, and the ionic strength on the environment. The experimental results demonstrated that an increase in the adsorbed amount of GOx on the OTCE can be achieved when the potential was applied. Although the increase in the adsorbed amount was examined as a function of the potential, a maximum enzymatic activity was observed in the GOx/OTCE substrate achieved at +800mV. These experiments suggest that although an increase in the amount of enzyme adsorbed can be obtained by the application of an external potential to the electrode, the magnitude of such potential can produce detrimental effects in the conformation of the adsorbed protein and should be carefully considered. As such, the article describes a simple and rational approach to increase the amount of enzyme adsorbed on a surface and can be applied to improve the sensitivity of a variety of biosensors.


Asunto(s)
Simulación por Computador , Glucosa Oxidasa/metabolismo , Adsorción , Catálisis , Electroquímica , Glucosa Oxidasa/química , Concentración de Iones de Hidrógeno
13.
J Steroid Biochem Mol Biol ; 144 Pt B: 294-303, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25086299

RESUMEN

The steroidal drug Tibolone is used for the treatment of climacteric symptoms and osteoporosis in post-menopausal women. Although Tibolone has been shown to exert neuroprotective actions after middle cerebral artery occlusion, its specific actions on glial cells have received very little attention. In the present study we have assessed whether Tibolone exerts protective actions in a human astrocyte cell model, the T98G cells, subjected to glucose deprivation. Our findings indicate that Tibolone decreases the effects of glucose deprivation on cell death, nuclear fragmentation, superoxide ion production, mitochondrial membrane potential, cytoplasmic calcium concentration and morphological parameters. These findings suggest that glial cells may participate in the neuroprotective actions of Tibolone in the brain.


Asunto(s)
Astrocitos/efectos de los fármacos , Moduladores de los Receptores de Estrógeno/farmacología , Glucosa/metabolismo , Fármacos Neuroprotectores/farmacología , Norpregnenos/farmacología , Astrocitos/metabolismo , Astrocitos/fisiología , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
14.
Neurosci Lett ; 565: 2-6, 2014 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-24394907

RESUMEN

Cortical spreading depression (CSD) is a presumably pathophysiological phenomenon that interrupts local cortical function for periods of minutes to hours. This phenomenon is important due to its association with different neurological disorders such as migraine, malignant stroke and traumatic brain injury (TBI). Glial cells, especially astrocytes, play an important role in the regulation of CSD and in the protection of neurons under brain trauma. The correlation of TBI with CSD and the astrocytic function under these conditions remain unclear. This review discusses the possible link of TBI and CSD and its implication for neuronal survival. Additionally, we highlight the importance of astrocytic function for brain protection, and suggest possible therapeutic strategies targeting astrocytes to improve the outcome following TBI-associated CSD.


Asunto(s)
Astrocitos/fisiología , Lesiones Encefálicas/fisiopatología , Depresión de Propagación Cortical , Animales , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Supervivencia Celular , Metabolismo Energético , Aminoácidos Excitadores/metabolismo , Humanos , Neuronas/patología , Neuronas/fisiología , Especies Reactivas de Oxígeno/metabolismo
15.
Neurosci Lett ; 558: 87-90, 2014 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-24246901

RESUMEN

Cortical spreading depression (CSD) is a depolarization wave associated with neurological disorders such as migraine, cerebral ischemia and traumatic brain injury. The mechanism of action of this phenomenon still remains unclear. Although it is suggested that extracellular K(+) accumulation contributes to CSD, other ions may play a relevant role in the mechanism of propagation of the wave. In this context, we hypothesize that Ca(2+) may play an important function in the wave propagation. Our results demonstrate that enhancing Ca(2+) influx into the cells by topical cortical application of the ionophore A23187 (10 µM, 50 µM and 100 µM solutions) increases the velocity of CSD propagation in a dose-dependent manner, and a much higher dose of this compound (2 mM) triggers CSD. In conclusion, increased Ca(2+) influx can be a key element in the induction mechanism of the CSD, and should be assessed in further experimental strategies targeting brain disorders related to CSD.


Asunto(s)
Calcio/metabolismo , Depresión de Propagación Cortical , Animales , Calcimicina/farmacología , Ionóforos de Calcio/farmacología , Masculino , Ratas Wistar
16.
J Theor Biol ; 345: 43-51, 2014 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-24361327

RESUMEN

GRP78 participates in multiple functions in the cell during normal and pathological conditions, controlling calcium homeostasis, protein folding and Unfolded Protein Response. GRP78 is located in the endoplasmic reticulum, but it can change its location under stress, hypoxic and apoptotic conditions. NF-κB represents the keystone of the inflammatory process and regulates the transcription of several genes related with apoptosis, differentiation, and cell growth. The possible relationship between GRP78-NF-κB could support and explain several mechanisms that may regulate a variety of cell functions, especially following brain injuries. Although several reports show interactions between NF-κB and Heat Shock Proteins family members, there is a lack of information on how GRP78 may be interacting with NF-κB, and possibly regulating its downstream activation. Therefore, we assessed the computational predictions of the GRP78 (Chain A) and NF-κB complex (IkB alpha and p65) protein-protein interactions. The interaction interface of the docking model showed that the amino acids ASN 47, GLU 215, GLY 403 of GRP78 and THR 54, ASN 182 and HIS 184 of NF-κB are key residues involved in the docking. The electrostatic field between GRP78-NF-κB interfaces and Molecular Dynamic simulations support the possible interaction between the proteins. In conclusion, this work shed some light in the possible GRP78-NF-κB complex indicating key residues in this crosstalk, which may be used as an input for better drug design strategy targeting NF-κB downstream signaling as a new therapeutic approach following brain injuries.


Asunto(s)
Lesiones Encefálicas/metabolismo , Proteínas de Choque Térmico/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Biología Computacional/métodos , Chaperón BiP del Retículo Endoplásmico , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular/métodos , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/fisiología , Mapeo de Interacción de Proteínas/métodos , Electricidad Estática
17.
Cell Biol Int ; 37(6): 521-32, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23494837

RESUMEN

Glucose-regulated protein 78 (GRP78; 78 kDa) belongs to a group of highly conserved heat shock proteins (Hsp) with important functions at the cellular level. The emerging interest for GRP78 relies on its different functions, both in normal and pathological circumstances. GRP78 regulates intracellular calcium, protein shaping, endoplasmic reticulum (ER) stress and cell survival by an immediate response to insults, and that its expression may also be regulated by estrogens. Although these roles are well explored, the mechanisms by which GRP78 induces these changes are not completely understood. In this review, we highlight various aspects related to the GRP78 functioning in cellular protection and repair in response to ER stress and unfolded protein response by the regulation of intracellular Ca(2+) and other mechanisms. In this respect, the novel interactions between GRP78 and estrogens, such as estradiol and others, are analyzed in the context of the central nervous system (CNS). We also discuss the importance of GRP78 and estrogens in brain diseases including ischemia, Alzheimer's and Huntington's disorders. Finally, the main protective mechanisms of GRP78 and estrogens during ER dysfunction in the brain are described, and the prospective roles of GRP78 in therapeutic processes.


Asunto(s)
Encéfalo/metabolismo , Estrógenos/metabolismo , Proteínas de Choque Térmico/metabolismo , Respuesta de Proteína Desplegada/fisiología , Animales , Sitios de Unión , Calcio/metabolismo , Chaperón BiP del Retículo Endoplásmico , Humanos
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