RESUMEN
Although women are at higher risk for Alzheimer's disease and other tauopathies, the underlying mechanisms are unclear. In this issue of Cell, Yan et al. show that aberrantly high activity of X-linked USP11 deubiquitinase in women impairs clearance of tau, the principal component of neurofibrillary tangles in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Enfermedad de Alzheimer/genética , Enzimas Desubicuitinizantes , Femenino , Humanos , Ovillos Neurofibrilares , Tioléster Hidrolasas , Proteínas tau/genéticaRESUMEN
Hydrogen sulfide (H(2)S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H(2)S is predominantly formed from Cys or its derivatives by the enzymes cystathionine ß-synthase and cystathionine γ-lyase. One of the mechanisms by which H(2)S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.
Asunto(s)
Cistationina betasintasa/metabolismo , Cistationina gamma-Liasa/metabolismo , Cisteína , Sulfuro de Hidrógeno/metabolismo , Proteínas , Animales , Cistationina betasintasa/química , Cistationina gamma-Liasa/química , Cisteína/química , Cisteína/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Gases/química , Gases/metabolismo , Humanos , Sulfuro de Hidrógeno/química , Inflamación/metabolismo , Proteínas/química , Proteínas/metabolismo , Transducción de Señal , Vasodilatación/fisiologíaRESUMEN
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.
Asunto(s)
COVID-19/metabolismo , Encefalomielitis/metabolismo , Síndrome de Fatiga Crónica/metabolismo , Animales , COVID-19/complicaciones , COVID-19/etiología , COVID-19/inmunología , Encefalomielitis/inmunología , Síndrome de Fatiga Crónica/inmunología , Humanos , Oxidación-Reducción , Síndrome Post Agudo de COVID-19RESUMEN
Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3ß (GSK3ß). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cistationina gamma-Liasa/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Sulfuro de Hidrógeno/farmacología , Morfolinas/farmacología , Fármacos Neuroprotectores/farmacología , Compuestos Organotiofosforados/farmacología , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Cistationina gamma-Liasa/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HEK293 , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Mutación , Ovillos Neurofibrilares/efectos de los fármacos , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Fosforilación , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/prevención & control , Unión Proteica , Procesamiento Proteico-Postraduccional , Sulfatos/metabolismo , Proteínas tau/metabolismoRESUMEN
Phosphorylation of histone H2AX is a major contributor to efficient DNA repair. We recently reported neurobehavioral deficits in mice lacking H2AX. Here we establish that this neural failure stems from impairment of mitochondrial function and repression of the mitochondrial biogenesis gene PGC-1α. H2AX loss leads to reduced levels of the major subunits of the mitochondrial respiratory complexes in mouse embryonic fibroblasts and in the striatum, a brain region particularly vulnerable to mitochondrial damage. These defects are substantiated by disruption of the mitochondrial shape in H2AX mutant cells. Ectopic expression of PGC-1α restores mitochondrial oxidative phosphorylation complexes and mitigates cell death. H2AX knockout mice display increased neuronal death in the brain when challenged with 3-nitropronionic acid, which targets mitochondria. This study establishes a role for H2AX in mitochondrial homeostasis associated with neuroprotection.
Asunto(s)
Histonas/metabolismo , Mitocondrias/metabolismo , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Fosforilación Oxidativa , Animales , Muerte Celular , Transporte de Electrón/fisiología , Histonas/genética , Ratones , Ratones Noqueados , Mitocondrias/genética , Células-Madre Neurales/citología , Neuronas/citología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , FosforilaciónRESUMEN
Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one-third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate and could influence synaptic excitability. We find that drugs that inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory postsynaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.
Asunto(s)
Glutatión/metabolismo , Sinapsis/metabolismo , Animales , Células Cultivadas , Potenciales Postsinápticos Excitadores/fisiología , Ácido Glutámico/metabolismo , Homeostasis , Neuronas/fisiología , Ratas Sprague-Dawley , Transmisión Sináptica/fisiologíaRESUMEN
Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Golgi stressor monensin acts via the PKR-like ER kinase/Activating Transcription Factor 4 pathway. ATF4 is the master regulator of amino acid metabolism, which is induced during amino acid depletion and other forms of stress. One of the genes regulated by ATF4 is the biosynthetic enzyme for cysteine, cystathionine γ-lyase (CSE), which also plays central roles in maintenance of redox homeostasis. Huntington's disease (HD), a neurodegenerative disorder, is associated with disrupted cysteine metabolism caused by depletion of CSE leading to abnormal redox balance and stress response. Thus, restoring CSE function and cysteine disposition may be beneficial in HD. Accordingly, we harnessed the monensin-ATF4-signaling cascade to stimulate CSE expression by preconditioning cells with monensin, which restores cysteine metabolism and an optimal stress response in HD. These findings have implications for treatment of HD and other diseases associated with redox imbalance and dysregulated ATF4 signaling.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Cistationina gamma-Liasa/metabolismo , Aparato de Golgi/metabolismo , Enfermedad de Huntington/metabolismo , Animales , Línea Celular , Cisteína/metabolismo , Ratones , Monensina , Estrés FisiológicoRESUMEN
Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.
Asunto(s)
Cistationina gamma-Liasa/deficiencia , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/patología , Animales , Encéfalo/enzimología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Cistationina gamma-Liasa/genética , Cisteína/administración & dosificación , Cisteína/biosíntesis , Cisteína/farmacología , Cisteína/uso terapéutico , Suplementos Dietéticos , Modelos Animales de Enfermedad , Agua Potable/química , Eliminación de Gen , Regulación Enzimológica de la Expresión Génica/genética , Proteína Huntingtina , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , Masculino , Ratones , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Factor de Transcripción Sp1/antagonistas & inhibidores , Factor de Transcripción Sp1/metabolismo , Transcripción Genética/genéticaRESUMEN
Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-κB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF-κB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-α treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-κB are markedly diminished. Thus, sulfhydration of NF-κB appears to be a physiologic determinant of its antiapoptotic transcriptional activity.
Asunto(s)
Apoptosis/fisiología , Sulfuro de Hidrógeno/química , FN-kappa B/química , Animales , Cistationina gamma-Liasa/genética , Cistationina gamma-Liasa/metabolismo , Cistationina gamma-Liasa/fisiología , Regulación de la Expresión Génica , Ratones , FN-kappa B/fisiología , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción ReIA/química , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Hydrogen sulfide (H2S) is a member of the growing family of gasotransmitters. Once regarded as a noxious molecule predominantly present in the atmosphere, H2S is now known to be synthesized endogenously in mammals. H2S participates in a myriad of physiological processes ranging from regulation of blood pressure to neuroprotection. Its chemical nature precludes H2S from being stored in vesicles and acting on receptor proteins in the fashion of other chemical messengers. Thus, novel cellular mechanisms have evolved to mediate its effects. This review focuses on sulfhydration (or persulfidation), which appears to be the principal post-translational modification elicited by H2S.
Asunto(s)
Gasotransmisores/metabolismo , Sulfuro de Hidrógeno/metabolismo , Transducción de SeñalRESUMEN
Disturbances in amino acid metabolism, which have been observed in Huntington's disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.
Asunto(s)
Aminoácidos/metabolismo , Regulación de la Expresión Génica , Homeostasis/genética , Enfermedad de Huntington/genética , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Línea Celular , Células Cultivadas , Cistationina gamma-Liasa/deficiencia , Cistationina gamma-Liasa/genética , Cisteína/metabolismo , Humanos , Enfermedad de Huntington/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/genética , Estrés OxidativoRESUMEN
p53 has been implicated in the pathophysiology of Huntington's disease (HD). Nonetheless, the molecular mechanism of how p53 may play a unique role in the pathology remains elusive. To address this question at the molecular and cellular biology levels, we initially screened differentially expressed molecules specifically dependent on p53 in a HD animal model. Among the candidate molecules, wild-type p53-induced gene 1 (Wig1) is markedly upregulated in the cerebral cortex of HD patients. Wig1 preferentially upregulates the level of mutant Huntingtin (Htt) compared with wild-type Htt. This allele-specific characteristic of Wig1 is likely to be explained by higher affinity binding to mutant Htt transcripts than normal counterpart for the stabilization. Knockdown of Wig1 level significantly ameliorates mutant Htt-elicited cytotoxicity and aggregate formation. Together, we propose that Wig1, a key p53 downstream molecule in HD condition, play an important role in stabilizing mutant Htt mRNA and thereby accelerating HD pathology in the mHtt-p53-Wig1 positive feedback manner.
Asunto(s)
Proteínas Portadoras/biosíntesis , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Proteínas Nucleares/biosíntesis , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Animales , Autopsia , Proteínas Portadoras/genética , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Enfermedad de Huntington/patología , Masculino , Ratones , Persona de Mediana Edad , Proteínas Mutantes/genética , Proteínas Nucleares/genética , ARN Mensajero/genética , Proteínas de Unión al ARNRESUMEN
Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.
Asunto(s)
Enfermedad de Huntington/enzimología , Enfermedad de Huntington/fisiopatología , Neuronas/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Adulto , Anciano , Animales , Biocatálisis , Demografía , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Estabilidad de Enzimas , Femenino , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Mitocondrias/metabolismo , Actividad Motora , Neostriado/enzimología , Neostriado/patología , Neostriado/fisiopatología , Neuronas/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Cambios Post Mortem , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Transcripción Genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Adipogenesis, the conversion of precursor cells into adipocytes, is associated with obesity and is mediated by glucocorticoids acting via hitherto poorly characterized mechanisms. Dexras1 is a small G protein of the Ras family discovered on the basis of its marked induction by the synthetic glucocorticoid dexamethasone. We show that Dexras1 mediates adipogenesis and diet-induced obesity. Adipogenic differentiation of 3T3-L1 cells is abolished with Dexras1 depletion, whereas overexpression of Dexras1 elicits adipogenesis. Adipogenesis is markedly reduced in mouse embryonic fibroblasts from Dexras1-deleted mice, whereas adiposity and diet-induced weight gain are diminished in the mutant mice.
Asunto(s)
Adipogénesis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Dexametasona/efectos adversos , Glucocorticoides/efectos adversos , Obesidad/inducido químicamente , Proteínas ras/metabolismo , Células 3T3-L1 , Adipogénesis/genética , Animales , Dexametasona/farmacología , Dieta/efectos adversos , Glucocorticoides/farmacología , Ratones , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Proteínas ras/genéticaRESUMEN
Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes.
Asunto(s)
Encéfalo/metabolismo , Epigénesis Genética/fisiología , Regulación de la Expresión Génica/fisiología , Genes Inmediatos-Precoces/fisiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Activación Transcripcional/fisiología , Análisis de Varianza , Animales , Proteína de Unión a CREB/metabolismo , Inmunoprecipitación de Cromatina , Regulación de la Expresión Génica/genética , Genes Inmediatos-Precoces/genética , Aprendizaje por Laberinto , Ratones , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Reconocimiento en Psicología/fisiologíaRESUMEN
D-Serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins, postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C terminus. SR also binds to the C terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity. AMPA receptor activation internalizes SR and disrupts its interaction with stargazin, therefore derepressing SR activity, leading to more D-serine production and potentially facilitating NMDA receptor activation. These interactions regulate the enzymatic activity as well as the intracellular localization of SR, potentially coupling the activities of NMDA and AMPA receptors. This shuttling of a neurotransmitter synthesizing enzyme between two receptors appears to be a novel mode of synaptic regulation.
Asunto(s)
Canales de Calcio/metabolismo , Ácido Glutámico/metabolismo , Guanilato-Quinasas/metabolismo , Proteínas de la Membrana/metabolismo , N-Metilaspartato/metabolismo , Racemasas y Epimerasas/metabolismo , Transmisión Sináptica , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Animales , Biocatálisis , Membrana Celular/metabolismo , Homólogo 4 de la Proteína Discs Large , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Modelos Biológicos , Unión Proteica , Ratas , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Biliverdin reductase-A (BVRA) is a multi-functional enzyme with a multitude of important roles in physiologic redox homeostasis. Classically, BVRA is well known for converting the heme metabolite biliverdin to bilirubin, which is a potent antioxidant in both the periphery and the brain. However, BVRA additionally participates in many neuroprotective signaling cascades in the brain that preserve cognition. Here, we review the neuroprotective roles of BVRA and bilirubin in the brain, which together constitute a BVRA/bilirubin axis that influences healthy aging and cognitive function.
Asunto(s)
Bilirrubina , Biliverdina , Encéfalo , Neuroprotección , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Bilirrubina/metabolismo , Biliverdina/metabolismo , Encéfalo/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Animales , RatonesRESUMEN
The ancient messenger molecule hydrogen sulfide (H2S) modulates myriad signaling cascades and has been conserved across evolutionary boundaries. Although traditionally known as an environmental toxin, H2S is also synthesized endogenously to exert modulatory and homeostatic effects in a broad array of physiologic functions. Notably, H2S levels are tightly physiologically regulated, as both its excess and paucity can be toxic. Accumulating evidence has revealed pivotal roles for H2S in neuroprotection and normal cognitive function, and H2S homeostasis is dysregulated in neurodegenerative conditions. Here, we review the normal neuroprotective roles of H2S that go awry in Alzheimer's disease, the most common form of neurodegenerative disease.
RESUMEN
Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3ß complex in response to insulin, hindering the accumulation of pGSK3ßS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3ßS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta , Resistencia a la Insulina , Insulina , Mitocondrias , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Transducción de Señal , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Mitocondrias/metabolismo , Fosforilación , Animales , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Insulina/metabolismo , Ratones , Humanos , Encéfalo/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Respuesta de Proteína Desplegada , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
The gaseous signaling molecule hydrogen sulfide (H2S) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H2S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions. Although toxic and even fatal at very high concentrations, emerging evidence has also revealed a pronounced neuroprotective role for lower doses of endogenously generated or exogenously administered H2S. Unlike traditional neurotransmitters, H2S is a gas and, therefore, is unable to be stored in vesicles for targeted delivery. Instead, it exerts its physiologic effects through the persulfidation/sulfhydration of target proteins on reactive cysteine residues. Here, we review the latest discoveries on the neuroprotective roles of H2S in Alzheimer's disease (AD) and traumatic brain injury, which is one the greatest risk factors for AD.