Albert Quintana

Autonomous University of Barcelona | UAB · Institute of Neuroscience (INc) Departament de Biologia Cel·lular, Fisiologia i Immunologia

Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein...

Mitochondrial dysfunction contributes to numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. We found that rapamycin, a specific inhi...

The striatum regulates motor control, reward and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G protein-coupled receptor GPR88 is robustly expressed in MSNs and is regulated by neuropharmacolo...

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with gliosis in several brain regions that usually results in infantile death. Loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, results in compromised activity of mitochondrial complex I as well as progressive neurodegenerative and behaviora...

To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by approximately 7 wk. Progressive neuronal deterior...

Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurod...

The cerebellum, a primary brain structure involved in the control of sensorimotor tasks, also contributes to higher cognitive functions including reward, emotion and social interaction. Although the regulation of these behaviors has been largely ascribed to the monoaminergic system in limbic regions, the contribution of cerebellar dopamine signalin...

Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive micro...

Passive motion can induce kinetosis (motion sickness, MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia and aversion to novel foods presented coinciden...

Mitochondrial diseases (MD), such as Leigh syndrome (LS), present with severe neurological and muscular phenotypes in patients, but have no known cure and limited treatment options. Based on their neuroprotective effects against other neurodegenerative diseases in vivo and their positive impact as an antioxidant against complex I deficiency in vitr...

Kisspeptin-expressing neurons in the rostral periventricular region of the third ventricle (RP3V) play an essential role in female reproduction. However, adult male mice were reported to have very few Kisspeptin-expressing neurons in the RP3V compared to females. This led to the hypothesis that Kiss1 RP3V neurons are responsible for the ability of...

An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1–4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5–10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins cont...

Respiratory dysfunction is among the main cause of severe and fatal pathologies worldwide. The use of effective experimental models and methodologies for the study of the pulmonary pathophysiology is necessary to prevent, control and cure these diseases. Plethysmography, a technique for the assessment of lung function, has been widely applied in mi...

Defects in mitochondrial function lead to severe neuromuscular orphan pathologies known as mitochondrial disease. Among them, Leigh Syndrome is the most common pediatric presentation, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death. Mitochondrial diseases are characterized by a marked anato...

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presen...

Defects in mitochondrial function lead to severe neuromuscular orphan pathologies known as mitochondrial disease. Among them, Leigh Syndrome is the most common pediatric presentation, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death. Mitochondrial diseases are characterized by a marked anato...

Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. F...

Ribosome tagging has become a very useful in vivo approach for analyzing gene expression and mRNA translation in specific cell types that are difficult and time consuming to isolate by conventional methods. The approach is based on selectively expressing a hemagglutinin A (HA)–tagged ribosomal protein in a target cell type and then using antibodies...

Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energy-requiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death....

Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal gang...

The striatum is anatomically and behaviorally implicated in behaviors that promote efficient foraging. To investigate this function, we studied instrumental choice behavior in mice lacking GPR88, a striatum-enriched orphan G-protein-coupled receptor that modulates striatal medium spiny neuron (MSN) excitability. Our results reveal that hungry mice...

An enigma of modern medicine has persisted for over 150 years. The mechanisms by which volatile anesthetics (VAs) produce their effects (loss of consciousness, analgesia, amnesia, and immobility) remain an unsolved mystery. Many attractive putative molecular targets have failed to produce a significant effect when genetically tested in whole-animal...

In the face of starvation, animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents, for example, will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors l...

Elevated fumarate concentrations as a result of Krebs cycle inhibition lead to increases in protein succination, an irreversible post-translational modification that occurs when fumarate reacts with cysteine residues to generate S-(2-succino)cysteine (2SC). Metabolic events that reduce NADH re-oxidation can block Krebs cycle activity; therefore we...

Hypothalamic neuronal populations are central regulators of energy homeostasis and reproductive function. However, the ontogeny of these critical hypothalamic neuronal populations is largely unknown. We developed a novel approach to examine the developmental pathways that link specific subtypes of neurons by combining embryonic and adult ribosome-t...

Interleukin-6 (IL-6) is a major cytokine controlling not only the immune system but also basic physiological variables such as body weight and metabolism. While central IL-6 is clearly implicated in the latter, the putative role of peripheral IL-6 controlling body weight remains unclear. We herewith report results obtained in muscle-specific IL-6 K...

Metallothioneins (MTs) are multipurpose proteins with clear antioxidant, anti-inflammatory and metal homeostasis properties. The roles of brain MT-1 and MT-2 are similar to those described in the periphery, and are inducible by metals, inflammatory and stress stimuli. MT-3, originally named growth inhibitory factor, exists mainly in the central ner...

Aim: Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, but because many types of cells can synthesize and respond to IL-6 considerable uncertainty still exists about the mechanisms underlying IL-6 effects. Therefore, the aim of this study was to analyse the effects of tissue-specific deletion of IL-6 using a fatty ac...

Mitochondrial dysfunction contributes to numerous health problems including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. Here, we report that rapamycin, a specifi...

Male spermatogenesis is a complex biological process that is regulated by hormonal signals from the hypothalamus (GnRH), the pituitary gonadotropins (LH and FSH) and the testis (androgens, inhibin). The two key somatic cell types of the testis, Leydig and Sertoli cells, respond to gonadotropins and androgens and regulate the development and maturat...

Sertoli and Leydig cell response to gonadotropin deprivation. Venn diagrams showing the number of transcripts with increased or decreased polysome association (1.5 fold or higher) after treatment with the GnRH antagonists cetrorelix (A) or acyline (B) in AMH-Cre: RiboTag mice, or with acyline in Cyp17iCre: RiboTag mice (C) by microarray analysis. T...

Leydig cell translational profile after 1 h of LH administration. (A) Heat map showing the regulation of transcripts with a 2-fold or higher increase after 1 h of LH stimulation (versus acyline treatment) in the Cyp17iCre: RiboTag IPs by microarray analysis. Only two transcripts (Bcl6 and Dppa4) showed a two-fold or greater decrease after LH stimul...

Leydig cell translational profile after 4 h of LH administration. (A) Heat map showing the regulation of transcripts with a 2-fold or higher increase after 4 h of LH administration (versus acyline treatment) in the Cyp17iCre: RiboTag IPs by microarray analysis. (B) Table shows the Leydig cell-specific (or highly enriched) transcripts (6-fold or hig...

Cluster analysis, Rps8 confirmation and phospho-S6 levels. (A) Cluster analysis of the microarray data obtained from IPs of Cyp17iCre: RiboTag mice treated as described. Transcripts that were significantly different between groups (p<0.01 using One-way Analysis of Variance (ANOVA)) were grouped into different clusters according to their response to...

Sertoli cell translational profile after FSH administration. (A) Serum levels for FSH and T after acyline and FSH administration (n = 3). Acyline was given for 3 d before FSH (1 u) administration for 1 h and 4 h. Data are the mean±SEM. Statistical analysis was performed using One-way Analysis of Variance (ANOVA) with Newman-Keuls multiple compariso...

Top 50 Sertoli cell-specific transcripts. To determine the top Sertoli cell-specific transcripts, microarray analysis of IPs and their respective inputs from AMH-Cre: RiboTag mouse testis (n = 5) was performed and the ratio of the signal in the IP to the input was calculated and expressed as enrichment. (DOCX)

Sertoli cell enriched genes. Transcripts that show a fold change >2 when comparing the signal in the IP to their respective inputs (enrichment) by microarray analysis in saline-treated AMH-Cre: RiboTag mice (n = 5) are listed. Statistical analysis was performed using One-way Analysis of Variance (ANOVA, p<0.05). (XLSX)

In vivo Sertoli-cell translational profile after testosterone (T) administration. (A) T and FSH serum levels in AMH-Cre: RiboTag mice treated with saline, Cetrorelix or Cetrorelix+testosterone (T) (n = 3). Cetrorelix (50 ug) was given s.c. for 3 d before a single i.p. injection of testosterone enanthate (10 mg). Serum was obtained 4 h after the T a...

qRT-PCR analysis of transcripts expressed at different levels in Leydig cells using inputs and IPs from Cyp17iCre: RiboTag mice. Mice were treated with saline, acyline, acyline+LH for 1 h and acyline+LH for 4 h (n = 4, from two independent experiments). Notice that analysis of the IP fraction allows for the detection of LH-induced changes in transc...

Enrichment analysis. Microarray analysis data of different transcripts from the Rgs (A), Stard (B), MCT (C), Fgfr (D), Tbx (E) and Aqp (F) family presented as fold change in the IPs versus the inputs (Enrichment) in untreated Cyp17iCre: RiboTag mice (n = 3). Data are the mean±SEM. (EPS)

Gene ontology analysis of Sertoli cell-specific or highly enriched transcripts. Transcripts that showed an enrichment (IP/I) ratio of 5 fold or higher in IPs from AMH-Cre: RiboTag mice testes were analyzed. GO categories with an AdjP value <0.05 are shown. (DOCX)

Sequences of primers used for qRT-PCR analysis. (DOCX)

Leydig cell enriched genes. Transcripts that show a fold change >2 when comparing the signal in the IP to their respective inputs (enrichment) by microarray analysis in Saline-treated Cyp17iCre: RiboTag mice (n = 3) are listed. Statistical analysis was performed using One-way Analysis of Variance (ANOVA, p<0.05). (XLSX)

Top 50 Leydig cell-specific transcripts. Leydig cell-specific transcripts were determined as described previously for Sertoli cells. Microarray analysis of Cyp17iCre: RiboTag mouse testis IPs and their respective inputs (n = 3) was performed and the enrichment was calculated as the ratio of the signal in the IPs compared to their inputs. (DOCX)

Kallikrein and Serpin family members enriched in Leydig cells. Table shows the members of the Kallikrein or Serpin family that have an enrichment (IP to input ratio) >4 in the Cyp17iCre: RiboTag pellets compared to their inputs by microarray analysis. Listed references confirm Leydig-cell specificity. (DOCX)

Gene ontology analysis of Leydig cell-specific or highly enriched transcripts. Transcripts that showed an enrichment (IP/I) ratio of 7 fold or higher in IPs from Cyp17iCre: RiboTag mouse testes were analyzed. GO categories with an AdjP value <0.01 are listed. (DOCX)

Supplemental experimental procedures. (DOCX)

Interleukin (IL)-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. While IL-6-deficient mice (IL-6 KO) are resistant to EAE, we showed previously that in transgenic mice with astrocyte-targeted production of IL-6-restricted to the ce...

Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physio...

Interleukin-6 (IL-6) is a major cytokine which controls not only the immune system but also exhibits many other functions including effects in the central nervous system (CNS). IL-6 is known to be produced by different cells in the CNS, and all the major CNS do respond to IL-6, which makes it difficult to dissect the specific roles of each cell typ...

Anesthetics are in routine use, yet the mechanisms underlying their function are incompletely understood. Studies in vitro demonstrate that both GABA(A) and NMDA receptors are modulated by anesthetics, but whole animal models have not supported the role of these receptors as sole effectors of general anesthesia. Findings in C. elegans and in childr...

Gene delivery vectors derived from adeno-associated virus (AAV) have great potential as therapeutic agents. rAAV1 and rAAV6, efficiently target striated muscle, but the mechanisms that determine their tropism remain unclear. It is known that AAV6, but not AAV1, interacts with heparin-sulfate proteoglycans (HSPG). HSPGs are not primary receptors for...

The striatum is composed predominantly of medium spiny neurons (MSNs) that integrate excitatory, glutamatergic inputs from the cortex and thalamus, and modulatory dopaminergic inputs from the ventral midbrain to influence behavior. Glutamatergic activation of AMPA, NMDA, and metabotropic receptors on MSNs is important for striatal development and f...

Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain region...

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the...

IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) w...

Endoplasmic reticulum (ER) stress has recently been proposed as one of the factors contributing to apoptotic cell death in Parkinson's disease (PD). Although MAO-B inhibitors have been suggested to exert neuroprotective effects in several experimental models of PD, their effectiveness against ER stress has not been fully determined. Therefore, we h...

Cryolesion of the frontoparietal cortex in mice is a well-described brain injury paradigm that results in increased astrogliosis surrounding the lesion site and is accompanied by a prominent increase in the MAO-B levels in astrocytes. Whether these increased MAO-B levels contribute to cellular damage or modulate reactive astrocytosis remains unclea...

PF9601N [N-(2-propynyl) 2-(5-benzyloxyindol) methylamine] is a non-amphetamine type MAO-B inhibitor that has shown neuroprotective properties in vivo using different experimental models of Parkinson's disease. The mechanisms underlying its neuroprotective effects are poorly understood, but appear to be independent of MAO-B inhibition. We have studi...

Interleukin-6 (IL-6) is one of the key players in the response of the brain cortex to injury. We have described previously that astrocyte-driven production of IL-6 (GFAP-IL6) in transgenic mice, although causing spontaneous neuroinflammation and long term damage, is beneficial after an acute (freeze) injury in the cortex, increasing healing and dec...