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January 2000 - present
Publications
Publications (68)
Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2 , the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This incre...
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like s...
Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased l...
A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work...
Tambaleante (tbl/tbl) is a mutant mouse that carries a spontaneous Gly483Glu substitution in the HERC1 (HECT domain and RCC1 domain) E3 ubiquitin ligase protein (HERC1). The tbl/tbl mutant suffers an ataxic syndrome given the almost complete loss of cerebellar Purkinje cells during adult life. More recent analyses have identified alterations at neu...
Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent incre...
Little is known about the functions of downstream regulatory element antagonist modulator (DREAM) in embryonic stem cells (ESCs). However, DREAM interacts with cAMP response element-binding protein (CREB) in a Ca2+-dependent manner, preventing CREB binding protein (CBP) recruitment. Furthermore, CREB and CBP are involved in maintaining ESC self-ren...
Aging is a progressive loss of physiological properties that drive to a decrease of functions and survival. Indeed, aging is the main risk factor for cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. The discovery that the rate of aging is controlled by conserved genetic and biochemical pathways has provoked an unprecedente...
Background: Fibromyalgia (FM) is a world-wide diffuse musculoskeletal chronic pain condition that affects up to 5% of the general population. Many symptoms associated with mitochondrial diseases are reported in FM patients such as exercise intolerance, fatigue, myopathy and mitochondrial dysfunction. In this study, we report a mutation cytochrome b...
Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored mem...
Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study show the implication of NLRP3-inflammasome in animal model of stress-induced depression. Accordingly,...
Aims: Impairment in AMP-activated protein kinase (AMPK) activity and NLRP3-inflammasome activation are associated with several metabolic and inflammatory diseases. Herein, we investigated the role of AMPK/NLRP3-inflammasome axis in the molecular mechanism underlying pain perception. Results: Impairment in AMPK activation induced by Compound C or su...
The ubiquitin-proteasome system (UPS) plays a fundamental role in protein degradation in neurons, and there is strong evidence that it fulfills a key role in synaptic transmission. The aim of the present work was to study the implication of one component of the UPS, the HERC1 E3 Ubiquitin Ligase, in motor function and neuromuscular transmission. Th...
Impaired AMPK is associated with a wide spectrum of clinical and pathological conditions, ranging from obesity, altered responses to exercise or metabolic syndrome, to inflammation, disturbed mitochondrial biogenesis and defective response to energy stress. Fibromyalgia (FM) is a world-wide diffused musculoskeletal chronic pain condition that affec...
Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress, mitochondrial dysfunction and inflammation may have a role in the pathophysiology of fibromyalgia. Despite several skin-related symptoms accompanied by small fiber neuropathy have been studied in FM, these mito...
There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X-ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning a...
A mutation in the HERC2 gene has been linked to a severe neurodevelopmental disorder with similarities to the Angelman syndrome. This gene codifies a protein with ubiquitin ligase activity that regulates the activity of tumor protein p53 and is involved in important cellular processes such as DNA repair, cell cycle, cancer, and iron metabolism. Des...
Synaptic plasticity is an essential process for information acquisition and storage. Previous studies have shown that changes in the expression of synaptic proteins may play a key role in learning and memory. The aim of this work is to identify changes in synaptic remodeling as well as alterations in the balance of excitatory and inhibitory synapse...
Aims:
Fibromyalgia (FM) is a prevalent chronic pain syndrome characterized by generalized hyperalgesia associated with a wide spectrum of symptoms such as fatigue and joint stiffness. Diagnosis of FM is difficult due to the lack of reliable diagnostic biomarkers, while treatment is largely inadequate. We have investigated the role of coenzyme Q10...
Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology. We have investigat...
Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress and inflammation in FM. We studied thirty women diagn...
Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that mitochondrial dysfunction and oxidative stress may have a role in the pathophysiology of FM. Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ10 levels...
A characteristic of higher organisms is their ability to learn by experience in order to adapt their
behaviour. Such plasticity is largely the result of the brain’s ability to convert transient stimuli into long-lasting
alterations in neuronal structure and function. This process is complex and involves changes in receptor
trafficking, local mRN...
Postnatal proteasome treatment caused no morphological alterations at PD15. At PD15, mice treated with proteasome inhibitors or the vehicle alone were sacrificed, and their brain histology was analysed. A–C Immunohistochemistry for calbindin revealed no differences in hippocampal dendritic morphology (A) in either the cerebellum (B) or amygdala (C)...
Proteasome inhibition during early postnatal development does not induce motor behaviour or morphological alterations in the spinal cord of adult mice. A–C, Motor function in adult mice that were treated with proteasome inhibitors during early life was measured by their performance in the rotarod (A), treadmill (B) and grip strength (C) tests. D, R...
Detailed description of neonatal behavioural tests included in the Fox battery.
(DOC)
Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering...
We examined lipid peroxidation (LPO) in blood mononuclear cells (BMCs) and plasma, as a marker of oxidative damage, and its association to clinical symptoms in Fibromyalgia (FM) patients.
We conducted a case-control and correlational study comparing 65 patients and 45 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impac...
Postnatal proteasome inhibition had no effect on body weight or neurobehavioural activity. A The body weight of animals treated with proteasome inhibitors evolved similarly to that of mice that received the vehicle alone, except for a small decrease in P9-10 mice treated with MG132 [t (28) = 2.233, P = 0.034], which was subsequently reversed. B–E,...
Total object exploration times (in seconds) of wt or dream−/− mice treated with vehicle or the drug indicated 15 min before the 5-minute OR memory training session. STM, short-term memory; LTM, long-term memory.
(DOC)
Total object exploration times (in seconds) of wt or dream−/− mice treated with vehicle or the drug indicated 15 min before the 5-minute OR memory training session. STM, short-term memory.
(DOC)
Synaptic plasticity involves short- and long-term events, although the molecular mechanisms that underlie these processes are not fully understood. The transient A-type K(+) current (I(A)) controls the excitability of the dendrites from CA1 pyramidal neurons by regulating the back-propagation of action potentials and shaping synaptic input. Here, w...
Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive deficits in patients...
Every other day feeding (EOD) and exercise induce changes in cell metabolism. The aim of the present work was to know if both EOD and exercise produce similar effects on physical capacity, studying their physiological, biochemical and metabolic effects on muscle. Male OF-1 mice were fed either ad libitum (AL) or under EOD. After 18 weeks under EOD,...
Memory formation requires changes in gene expression, which are regulated by the activation of transcription factors and by changes in epigenetic factors. Poly[ADP]-ribosylation of nuclear proteins has been postulated as a chromatin modification involved in memory consolidation, although the mechanisms involved are not well characterized. Here we d...
Neuropsychological analyses of amnesic patients, as well as lesion experiments, indicate that the temporal lobe is essential for the encoding, storage, and expression of object recognition memory (ORM). However, temporal lobe structures directly involved in the consolidation and reconsolidation of these memories are not yet well-defined. We report...
Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis. We have previously identified DREAM (downstre...
Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes
associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central
nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasti...
Histone deacetylases (HDAC) are enzymes that maintain chromatin in a condensate state, related with absence of transcription. We have studied the role of HDAC on learning and memory processes. Both eyeblink classical conditioning (EBCC) and object recognition memory (ORM) induced an increase in histone H3 acetylation (Ac-H3). Systemic treatment wit...
Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor t...
One of the main focal points of aging research is the search for treatments that will prevent or ameliorate the learning and memory deficiencies associated with aging. Here we have examined the effects of maintaining mature mice on a long-term intermittent fasting diet (L-IFD). We found that L-IFD enhances learning and consolidation processes. We a...
We studied the effects of a selective lesion in rats, with 192-IgG-saporin, of the cholinergic neurons located in the medial septum/diagonal band (MSDB) complex on the acquisition of classical and instrumental conditioning paradigms. The MSDB lesion induced a marked deficit in the acquisition, but not in the retrieval, of eyeblink classical conditi...
Memory, as measured by changes in an animal's behavior some time after learning, is a reflection of many processes. Here, using a trace paradigm, in mice we show that de novo protein synthesis is required for acquisition, consolidation, reconsolidation, and extinction of classically conditioned eyelid responses. Two critical periods of protein synt...
Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Here we show that mice subjected to an intermittent fasting diet (IFD) display markedly reduced responses in models of thermal and visceral pain compared with mice fed ad libitum (AL). Pharmacological analyses...
Prodynorphin transcription has been postulated as an important molecular mechanism involved in adaptation/repair processes. Expression of prodynorphin is modulated according to the levels of the second messengers cAMP and Ca(2+). In the neuroblastoma cell lines, the increase of prodynorphin mRNA levels is coupled to an elevation of intracellular cA...
Protein kinase A-dependent derepression of the human prodynorphin gene is regulated by the differential occupancy of the Dyn
downstream regulatory element (DRE) site. Here, we show that a direct protein-protein interaction between DREAM and the CREM
repressor isoform, αCREM, prevents binding of DREAM to the DRE and suggests a mechanism for cyclic A...
Transcriptional repressor DREAM, an EF-hand containing calcium-binding protein, blocks basal expression of target genes through specific interaction with DRE sites in the DNA. The sequence GTCA forms the central core of the DRE site, whereas flanking nucleotides contribute notably to the affinity for DREAM. Release of binding of DREAM from the DRE...
Fluxes in amounts of intracellular calcium ions are important determinants of gene expression. So far, Ca2+-regulated kinases and phosphatases have been implicated in changing the phosphorylation status of key transcription factors and thereby modulating their function. In addition, direct effectors of Ca2+-induced gene expression have been suggest...
Induction of the prodynorphin gene has been implicated in medium and long-term adaptation during memory acquisition and pain. By 5' deletion mapping and site-directed mutagenesis of the human prodynorphin promoter, we demonstrate that both basal transcription and protein kinase A (PKA)-induced transcription in NB69 and SK-N-MC human neuroblastoma c...
Induction of the prodynorphin gene occurs in a tissue-specific manner following different physiological stimuli. Using electrophoretic mobility shift assays, we studied the relative activity of the five major regulatory sites in the rat prodynorphin promoter. Prodynorphin cyclic AMP-responsive element 2 (DynCRE2), DynCRE3, and the noncanonical prod...
Peripheral noxious stimulation is known to trigger signalling cascades in neurons of the spinal cord. The response to pain and stress at the level of gene expression involves transcriptional activation of several cyclic AMP responsive genes. Here, we show induction of the CREM (cyclic-AMP responsive element modulator) gene in distinct subpopulation...
Induction of early genes occurs in spinal cord upon arrival of nociceptive stimuli. Early genes have been proposed as third messengers in intracellular signaling since they couple changes in second messengers with changes in gene expression which will be the base for short and long-term memory processes. The prodynorphin promoter includes an AP-1 s...
Referencia OEPM: P9802667.-- Fecha de solicitud: 22/12/1998.-- Titular: Consejo Superior de Investigaciones Científicas (CSIC). Polipéptido DREAM, nueva proteína reguladora de la expresión génica. Esta invención hace referencia a un factor de transcripción represor de la expresión de genes por su unión a las secuencias DRE, denominado DREAM (DRE An...
