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The theory that aging is driven by the damage produced by reactive oxygen species (ROS) derived from oxidative metabolism dominated geroscience studies during the second half of the 20th century. However, increasing evidence that ROS also plays a key role in the physiological regulation of numerous processes through the reversible oxidation of cysteine residues in proteins, has challenged this notion. Currently, the scope of redox signaling has reached proteomic dimensions through mass spectrometry techniques. Here, we perform a comprehensive bioinformatics analysis of cysteine oxidation changes during mouse brain aging, using the quantitative data provided in the Oximouse dataset. Interestingly, our unbiased analysis identified hundreds of putative cysteine redox switches covering several pathways previously associated with aging. These include the ubiquitin-proteasome pathway and one-carbon metabolism (folate cycle, methionine cycle, transsulfuration and polyamine pathways). Surprisingly, cysteine oxidation changes are enriched in synaptic proteins in a highly asymmetric distribution: while postsynaptic proteins tend to increase cysteine oxidation with age, the opposite occurs for presynaptic proteins. Additionally, cysteine oxidation changes during aging are associated with proteins involved in the regulation of the mitochondrial transition pore opening and synaptic calcium homeostasis. Our analysis reinforces the concept that brain aging is associated with selective changes in the oxidation state of key proteins, rather than an overall trend toward increased oxidation. Also, we provide a prioritized list of specific cysteine residues with putative impact in aging processes for future experimental validation.
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Disfunción Cognitiva , Estrés Oxidativo , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Cisteína/metabolismo , Proteómica/métodos , Envejecimiento/metabolismo , Proteínas/metabolismo , Oxidación-Reducción , Encéfalo/metabolismoRESUMEN
Plants are the source of our understanding of several fundamental biological principles. It is well known that Gregor Mendel discovered the laws of Genetics in peas and that maize was used for the discovery of transposons by Barbara McClintock. Plant models are still useful for the understanding of general key biological concepts. In this article, we will focus on discussing the recent plant studies that have shed new light on the mysterious mechanisms of meiotic crossover (CO) interference, heterochiasmy, obligatory CO, and CO homeostasis. Obligatory CO is necessary for the equilibrated segregation of homologous chromosomes during meiosis. The tight control of the different male and female CO rates (heterochiasmy) enables both the maximization and minimization of genome shuffling. An integrative model can now predict these observed aspects of CO patterning in plants. The mechanism proposed considers the Synaptonemal Complex as a canalizing structure that allows the diffusion of a class I CO limiting factor linearly on synapsed bivalents. The coarsening of this limiting factor along the SC explains the interfering spacing between COs. The model explains the observed coordinated processes between synapsis, CO interference, CO insurance, and CO homeostasis. It also easily explains heterochiasmy just considering the different male and female SC lengths. This mechanism is expected to be conserved in other species.
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BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary ß and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders.
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Epilepsia , Canales de Potasio de Gran Conductancia Activados por el Calcio , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Genes vif , Neuronas/metabolismo , Membrana Celular/metabolismo , Epilepsia/genética , Calcio/metabolismoRESUMEN
Abstract Background Since schizophrenia is a multifactorial mental illness, a basic understanding of its etiological components improves its understanding, diagnosis, and the selection of therapeutic targets. Objective To identify the prodromes and biological markers in schizophrenic or ultra-high risk (UHR) patients and elucidate their specificity. Method Narrative review of relevant sources in English and Spanish in the Medline-PubMed database on minor physical abnormalities, cognitive abnormalities, neuroanatomical, and synaptic and cell changes present in schizophrenic patients and/or subjects with a high risk of developing schizophrenia Results Patients with SZ and, to a lesser extent, UHR subjects present phenotypic and behavioral manifestations that correlate with underlying cell processes. The study of the latter makes it possible to characterize diagnostic biomarkers. At present, its clinical application is limited by factors such as poorly understood pathophysiology, lack of study models, homology with other psychiatric disorders, and the dearth of clinical trials conducted. Discussion and conclusion Schizophrenia is the final manifestation of damage to prenatal and post-natal neurodevelopment and is reflected during the prodromal stage in early biological markers with clinical relevance. It is necessary to establish new study models that will increase knowledge to offer specific biomarkers for use in early clinical diagnosis.
Resumen Antecedentes La esquizofrenia es una enfermedad mental multifactorial. Una comprensión básica de sus componentes etiológicos mejora su entendimiento, su diagnóstico y la selección de posibles blancos terapéuticos. Objetivo Reportar los pródromos e indicadores biológicos en pacientes esquizofrénicos o de ultra-alto riesgo (UHR) y dilucidar su especificidad. Método Revisión narrativa de fuentes relevantes en inglés y español en la base de datos Medline-PubMed sobre las anomalías física menores, anomalías cognitivas, cambios neuroanatómicos, sinápticos y celulares presentes en pacientes esquizofrénicos y/o en sujetos de UHR. Resultados Los pacientes con EZ y, de manera menos predominante, los sujetos de UHR presentan manifestaciones fenotípicas y conductuales que se correlacionan con los procesos celulares subyacentes. El estudio de éstos permite caracterizar diferentes biomarcadores diagnósticos. En la actualidad, su aplicación en la clínica es limitada por distintos factores como son la fisiopatología poco comprendida, la falta de modelos de estudio, la homología con otros trastornos psiquiátricos y los escasos ensayos clínicos realizados. Discusión y conclusión La esquizofrenia es la manifestación final de daños en el neurodesarrollo prenatal y post-natal, y se refleja durante la etapa prodrómica en indicadores biológicos tempranos con relevancia clínica. Se requiere establecer nuevos modelos de estudio que permitan ampliar el conocimiento para ofrecer biomarcadores específicos para ser usados en el diagnóstico clínico temprano.
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α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson's Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aß) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.
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Isoquinolinas/farmacología , Neuronas/citología , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Animales , Benzotiazoles/farmacología , Células Cultivadas , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Unión Proteica , Dominios Proteicos , Ratas , Transmisión SinápticaRESUMEN
BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD. RESULTS: 177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction. CONCLUSIONS: Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad/genética , Aprendizaje/fisiología , Polimorfismo Genético/genética , Pruebas Genéticas/métodos , Variación Genética/genética , HumanosRESUMEN
During the first meiotic division, the segregation of homologous chromosomes depends on the physical association of the recombined homologous DNA molecules. The physical tension due to the sites of crossing-overs (COs) is essential for the meiotic spindle to segregate the connected homologous chromosomes to the opposite poles of the cell. This equilibrated partition of homologous chromosomes allows the first meiotic reductional division. Thus, the segregation of homologous chromosomes is dependent on their recombination. In this review, we will detail the recent advances in the knowledge of the mechanisms of recombination and bivalent formation in plants. In plants, the absence of meiotic checkpoints allows observation of subsequent meiotic events in absence of meiotic recombination or defective meiotic chromosomal axis formation such as univalent formation instead of bivalents. Recent discoveries, mainly made in Arabidopsis, rice, and maize, have highlighted the link between the machinery of double-strand break (DSB) formation and elements of the chromosomal axis. We will also discuss the implications of what we know about the mechanisms regulating the number and spacing of COs (obligate CO, CO homeostasis, and interference) in model and crop plants.
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La aparición progresiva de habilidades sensoriales, motoras y cognitivo-afectivas en el humano a lo largo de su desarrollo es un reflejo de cambios fisiológicos que se gestan al interior del sistema nervioso. Dichos cambios hacen parte de procesos dinámicos y dependen, después del nacimiento, de la actividad eléctrica inducida por la experiencia. Considerando lo anterior, el sistema nervioso en desarrollo constituye una especie de protomapa, sobre el que la experiencia moldea características moleculares, neuroquímicas y de conectividad, que se reflejan en las actividades emergentes del sistema. La evidencia que soporta la importancia que la influencia experiencial tiene sobre el desarrollo del sistema nervioso viene en aumento. Esta revisión reúne información sobre estudios en modelos biológicos y en humanos sometidos a privación sensorial y ambiental. Se enfatiza en la caracterización de los rasgos cognitivos y sociales.
The progressive advent of sensory, motor, affective, and cognitive skills in the human being through its development, demonstrate physiological changes that are gestated within the nervous system. These processes are dynamic and dependent postnatally on electrical activity induced by experience. Taking this into account, the developing nervous system constitutes a protomap molded by experience dependent molecular, physiological and connectivity characteristics, which are reflected in the emergent principles of the system. The evidence that supports the importance of experience as influence over the development of this system has increased in the past years. This document gathers information about animal models and human studies enduring sensory and environmental deprivation, emphasizing in the characterization of their cognitive and social remarks.
O aparecimento progressivo de habilidades sensoriais, motoras e cognitivo-afetivas no humano ao longo do seu desenvolvimento é um reflexo de mudanças fisiológicas que se gestam no interior do sistema nervoso. Ditas mudanças fazem parte de processos dinâmicos e dependem, depois do nascimento, da atividade elétrica induzida pela experiência. Considerando o anterior, o sistema nervoso em desenvolvimento constitui uma espécie de "protomapa", sobre o que a experiência molda características moleculares, neuroquímicas e de conectividade, que se refletem nas atividades emergentes do sistema. A evidência que suporta a importância que a influência experiencial tem sobre o desenvolvimento do sistema nervoso vem em aumento. Esta revisão reúne informação sobre estudos em modelos biológicos e em humanos submetidos a privação sensorial e ambiental. Se enfatiza na caracterização das características cognitivas e sociais.
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Humanos , Animales , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto , Trastornos del Neurodesarrollo , Reflejo , Privación Sensorial , Sinapsis , Cognición , Modelos Animales , Crecimiento y Desarrollo , Modelos Biológicos , Sistema Nervioso , Plasticidad NeuronalRESUMEN
The prefrontal cortex (PFC) is one of the brain regions with more prominent changes in human aging. The molecular processes related to the cognitive decline and mood changes during aging are not completely understood. To improve our knowledge, we integrated transcriptomic data of four studies of human PFC from elderly people (58â»80 years old) compared with younger people (20â»40 years old) using a meta-analytic approximation combined with molecular signature analysis. We identified 1817 differentially expressed genes, 561 up-regulated and 1256 down-regulated. Pathway analysis revealed down-regulation of synaptic genes with conservation of gene expression of other neuronal regions. Additionally, we identified up-regulation of markers of astrogliosis with transcriptomic signature compatible with A1 neurotoxic astrocytes and A2 neuroprotective astrocytes. Response to interferon is related to A1 astrocytes and the A2 phenotype is mediated in aging by activation of sonic hedgehog (SHH) pathway and up-regulation of metallothioneins I and genes of the family ERM (ezrin, radixin, and moesin). The main conclusions of our study are the confirmation of a global dysfunction of the synapses in the aged PFC and the evidence of opposite phenotypes of astrogliosis in the aging brain, which we report for the first time in the present article.
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Tau is an essential protein that physiologically promotes the assembly and stabilization of microtubules, and participates in neuronal development, axonal transport, and neuronal polarity. However, in a number of neurodegenerative diseases, including Alzheimer's disease (AD), tau undergoes pathological modifications in which soluble tau assembles into insoluble filaments, leading to synaptic failure and neurodegeneration. Mitochondria are responsible for energy supply, detoxification, and communication in brain cells, and important evidence suggests that mitochondrial failure could have a pivotal role in the pathogenesis of AD. In this context, our group and others investigated the negative effects of tau pathology on specific neuronal functions. In particular, we observed that the presence of these tau forms could affect mitochondrial function at three different levels: (i) mitochondrial transport, (ii) morphology, and (iii) bioenergetics. Therefore, mitochondrial dysfunction mediated by anomalous tau modifications represents a novel mechanism by which these forms contribute to the pathogenesis of AD. In this review, we will discuss the main results reported on pathological tau modifications and their effects on mitochondrial function and their importance for the synaptic communication and neurodegeneration.
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Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aß) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-ß (Aß) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-ß (oAß(1-42)). We showed that oAß(1-42) exposure significantly decreased the density of mature (mushroom shaped) dendritic spines density and synaptic contacts number. oAß(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiology and highlight its potential as an alternative pharmacological strategy for AD.
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Péptidos beta-Amiloides/farmacología , Benzoatos/farmacología , Bencilaminas/farmacología , Hipocampo/citología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Sinapsis/efectos de los fármacos , Animales , Células Cultivadas , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Embrión de Mamíferos , Regulación de la Expresión Génica/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Receptores X del Hígado/agonistas , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Proteínas Quinasas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinaptotagmina I/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
Water-homeostasis is a fundamental physiological process for terrestrial life. In vertebrates, thirst drives water intake, but the neuronal circuits that connect the physiology of water regulation with emotional context are poorly understood. Vasopressin (VP) is a prominent messenger in this circuit, as well as L-glutamate. We have investigated the role of a VP circuit and interaction between thirst and motivational behaviors evoked by life-threatening stimuli in rats. We demonstrate a direct pathway from hypothalamic paraventricular VP-expressing, glutamatergic magnocellular neurons to the medial division of lateral habenula (LHbM), a region containing GABAergic neurons. In vivo recording and juxtacellular labeling revealed that GABAergic neurons in the LHbM had locally branching axons, and received VP-positive axon terminal contacts on their dendrites. Water deprivation significantly reduced freezing and immobility behaviors evoked by innate fear and behavioral despair, respectively, accompanied by decreased Fos expression in the lateral habenula. Our results reveal a novel VP-expressing hypothalamus to the LHbM circuit that is likely to evoke GABA-mediated inhibition in the LHbM, which promotes escape behavior during stress coping.