المؤلفون: Marco Rasile, Eliana Lauranzano, Elisa Faggiani, Margherita M Ravanelli, Federico S Colombo, Filippo Mirabella, Irene Corradini, Maria L Malosio, Antonella Borreca, Elisa Focchi, Davide Pozzi, Toni Giorgino, Isabella Barajon, Michela Matteoli

المصدر: EMBO J

مصطلحات موضوعية: General Immunology and Microbiology, General Neuroscience, Corrigendum, Molecular Biology, General Biochemistry, Genetics and Molecular Biology

الوصف: [Image: see text]

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd4951738b4d30063102d8a39fca10e7Test
https://europepmc.org/articles/PMC10183814Test/

المؤلفون: Marco Rasile, Eliana Lauranzano, Elisa Faggiani, Margherita M Ravanelli, Federico S Colombo, Filippo Mirabella, Irene Corradini, Maria L Malosio, Antonella Borreca, Elisa Focchi, Davide Pozzi, Toni Giorgino, Isabella Barajon, Michela Matteoli

المصدر: The EMBO journal. 41(23)

مصطلحات موضوعية: Male, General Immunology and Microbiology, Behavior, Animal, General Neuroscience, Brain, Endothelial Cells, General Biochemistry, Genetics and Molecular Biology, Transforming Growth Factor beta1, Mice, Disease Models, Animal, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Animals, Female, Molecular Biology, Cerebral Hemorrhage

الوصف: Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF-β1 active form and the consequent enhancement of pSMAD1-5 in males' brain endothelial cells. TGF-β1, in combination with IL-1β, reduces the endothelial expression of CD146 and claudin-5, alters the endothelium-pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex-specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::410f0f17e2285abb0c063a51e3a4362cTest
https://pubmed.ncbi.nlm.nih.gov/36314682Test

المؤلفون: Filippo Mirabella, Marco Rasile, Eliana Lauranzano, Michela Matteoli

المصدر: The Febs Journal

مصطلحات موضوعية: 0301 basic medicine, Brain vasculature, Coronavirus disease 2019 (COVID-19), long‐COVID, Neuronal migration, State‐Of‐The‐Art Reviews, blood–brain barrier, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, COVID‐19, synapse, Animals, Humans, State‐Of‐The‐Art Review, Medicine, prenatal viral infection, Pregnancy Complications, Infectious, neurovascular unit, Perinatal infections, Molecular Biology, maternal immune activation, business.industry, Mental Disorders, Brain, COVID-19, Cell Biology, Neurovascular bundle, medicine.disease, cytokines, 030104 developmental biology, inflammation, Prenatal Exposure Delayed Effects, 030220 oncology & carcinogenesis, Damages, Etiology, Female, hemorrhage, business

الوصف: Intragravidic and perinatal infections, acting through either direct viral effect or immune‐mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up‐to‐date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID‐19 longitudinal studies.
Intragravidic and perinatal infections are recognized causes of liability for neurodevelopmental disorders in the progeny. This review aims to discuss the up‐to‐date evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e817ef187786eef526660ff0b0f216fTest
https://doi.org/10.1111/febs.16020Test

المؤلفون: Naim Panjwani, Amy Shakeshaft, Delnaz Roshandel, Fan Lin, Amber Collingwood, Anna Hall, Katherine Keenan, Celine Deneubourg, Filippo Mirabella, Simon Topp, Jana Zarubova, Rhys H. Thomas, Inga Talvik, Marte Syvertsen, Pasquale Striano, Anna B. Smith, Kaja K. Selmer, Guido Rubboli, Alessandro Orsini, Ching Ching Ng, Rikke S. Møller, Kheng Seang Lim, Khalid Hamandi, David A. Greenberg, Joanna Gesche, Elena Gardella, Choong Yi Fong, Christoph P. Beier, Danielle M. Andrade, Heinz Jungbluth, Mark P. Richardson, Annalisa Pastore, Manolis Fanto, Deb K. Pal, Lisa J. Strug

الوصف: Introductory ParagraphElevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and epilepsy1-5. We performed a genome-wide association, colocalization and pathway analysis of impulsivity in juvenile myoclonic epilepsy (JME). We identify genome-wide associated SNPs at 8q13.3 (p=7.5 × 10−9) and 10p11.21 (p=3.6 × 10−8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (p=9.5 × 10−3). SLCO5A1 codes for a membrane-bound organic anion transporter6 and upregulates synapse assembly/organisation genes7. Pathway analysis also demonstrates 9.3-fold enrichment for synaptic assembly genes (p=0.03) including NRXN1, NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila homolog of SLCO5A1, causes both over-reactive startling behaviour (p=8.7 × 10−3) and increased seizure-like events (p=6.8 × 10−7). Polygenic risk score for ADHD correlates with impulsivity scores (p=1.60 × 10−3), demonstrating shared genetic contributions. SLCO5A1 loss-of-function represents a novel impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ab9a5e8de725eeab42009941cb2b694eTest
https://doi.org/10.1101/2022.04.19.22273994Test

المؤلفون: Massimiliano Pagani, Davide Pozzi, Linda Scaramuzza, M. De Simone, D. Genni, Filippo Mirabella, Fabio Benfenati, Fabrizia Cesca, Nicoletta Landsberger, G. De Rocco, C. G. Clementina, Martina Chiacchiaretta, Paola Conforti, Francesco Bedogni

المساهمون: Scaramuzza, L., De Rocco, G., Desiato, G., Cobolli Gigli, C., Chiacchiaretta, M., Mirabella, F., Pozzi, D., De Simone, M., Conforti, P., Pagani, M., Benfenati, F., Cesca, F., Bedogni, F., Landsberger, N.

المصدر: EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 13, Iss 4, Pp n/a-n/a (2021)

مصطلحات موضوعية: 0301 basic medicine, Ampakine, Medicine (General), congenital, hereditary, and neonatal diseases and abnormalities, Offspring, medicine.drug_class, Methyl-CpG-Binding Protein 2, Rett syndrome, Biology, QH426-470, Article, neuronal activity, MECP2, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurodevelopmental disorder, R5-920, neuronal maturation, In vivo, Transcription (biology), medicine, Genetics, Premovement neuronal activity, Animals, Humans, Gene, Mecp2, 030304 developmental biology, Neurons, 0303 health sciences, Brain, Articles, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, nervous system, Molecular Medicine, Female, Genetics, Gene Therapy & Genetic Disease, Neuroscience, 030217 neurology & neurosurgery

الوصف: MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.
Neuronal activity drives transcriptional and morphological changes that ensure maturation. Such mechanism is affected by Mecp2 absence. We show the rescue effects produced by enhancing Mecp2 null neurons activity and propose new therapeutic time windows for the treatment of Rett syndrome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b09a6f93f9505c33ebd8d3fe0f3407bcTest
http://europepmc.org/articles/PMC8033520Test

المؤلفون: Marija Markicevic, Paolo Kunderfranco, Alberto Termanini, Davide Pozzi, Filippo Mirabella, Marco Rasile, Clara Akofa Amegandjin, Simona Lodato, Clelia Peano, Michela Matteoli, Genni Desiato, Valerio Zerbi, Giuliana Fossati, Elisabetta Menna, Christina Grimm, Sara Mancinelli, Raffaella Morini, Graziella Di Cristo

مصطلحات موضوعية: RGS4, Glutamatergic, Excitatory synapse, biology, Offspring, biology.protein, Hippocampal formation, STAT3, Interleukin 6, Neuroscience, Transcription factor

الوصف: SummaryEarly prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7bd141f83c545acf5b81f8742f8445c5Test
https://doi.org/10.1101/2020.11.02.364356Test

المؤلفون: Filippo Mirabella, Sara Mancinelli, Raffaella Morini, Marco Rasile, Clara Akofa Amegandjin, Simona Lodato, Davide Pozzi, Michela Matteoli, Marija Markicevic, Paolo Kunderfranco, Clelia Peano, Alberto Termanini, Genni Desiato, Valerio Zerbi, Giuliana Fossati, Elisabetta Menna, Christina Grimm, Graziella Di Cristo

المصدر: Immunity. 54(11)

مصطلحات موضوعية: Offspring, Immunology, Synaptogenesis, Hippocampal formation, Biology, Hippocampus, Synaptic Transmission, Glutamatergic, Mice, Neurodevelopmental disorder, Pregnancy, medicine, Immunology and Allergy, Animals, Neuroinflammation, Neurons, Interleukin-6, medicine.disease, Disease Models, Animal, Infectious Diseases, Maternal Exposure, Prenatal Exposure Delayed Effects, Synapses, Cytokines, Female, Glutamatergic synapse, Disease Susceptibility, Inflammation Mediators, Neuroscience, Signal Transduction

الوصف: Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::939830eead92fd551944b6e82bb15d8fTest
https://pubmed.ncbi.nlm.nih.gov/34758335Test

المؤلفون: Filippo Mirabella, Matteo Fossati, Alessandra Folci

المصدر: eneuro
eNeuro

مصطلحات موضوعية: Ubiquitin-Like Proteins, SUMO protein, Physiology, Review, ubiquitination, Synapse, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, neddylation, Ubiquitin, Intellectual disability, medicine, synapse function, Humans, Ubiquitins, 030304 developmental biology, 0303 health sciences, biology, General Neuroscience, sumoylation, General Medicine, medicine.disease, Crosstalk (biology), intellectual disability, Synapses, biology.protein, Disorders of the Nervous System, Neddylation, synapse development, 030217 neurology & neurosurgery

الوصف: Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a08495c09fe3999e84fcddee950f7cd5Test

المؤلفون: Fabia Filipello, Cecilia Gotti, Raffaella Morini, Davide Pozzi, Alice Canzi, Filippo Mirabella, Douglas S. Annis, Cecilia Garlanda, Michela Matteoli, Elisabetta Menna, Alberto Mantovani, Deane F. Mosher, Giuliana Fossati, Milena Moretti, Giulia Taraboletti, Elsa Ghirardini, Sonia Valentino, Barbara Bottazzi

المصدر: The EMBO Journal

مصطلحات موضوعية: Synaptogenesis, Nerve Tissue Proteins, CHO Cells, AMPA receptor, thrombospondin, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Thrombospondin 1, Synapse, Mice, 03 medical and health sciences, Cricetulus, astrocyte, 0302 clinical medicine, synapse, Cricetinae, Biological neural network, Animals, Receptors, AMPA, Thrombospondins, Molecular Biology, Cells, Cultured, PTX3, 030304 developmental biology, 0303 health sciences, Neuronal Plasticity, AMPARs, General Immunology and Microbiology, Integrin beta1, General Neuroscience, Glutamate receptor, Brain, Articles, Extracellular Matrix, Mice, Inbred C57BL, Protein Transport, C-Reactive Protein, Astrocytes, Synapses, Excitatory postsynaptic potential, Neuroscience, 030217 neurology & neurosurgery

الوصف: Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte‐secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post‐synaptically silent, suggesting that completion of early synaptogenesis may require a two‐step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally‐active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor‐induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1‐integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N‐terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aae0e51fd2c1e4e3ae29ea37b0aefe1bTest
https://doi.org/10.15252/embj.201899529Test

المؤلفون: Marco Morreale, Filippo Mirabella, Francesco Paolo La Mantia, Roberto Scaffaro

المصدر: Macromolecular Materials and Engineering. 296:141-150

مصطلحات موضوعية: chemistry.chemical_compound, Materials science, Lactide, Polymers and Plastics, Rheology, Chemical engineering, Scale (ratio), chemistry, General Chemical Engineering, Organic Chemistry, Materials Chemistry, macromolecular substances, Composite material

الوصف: Poly(lacticacid)(PLA)hasbeengainingarisinginterestoverthe last years as a biodegradable and environmental-friendly substitute of traditional non-biodegradable poly-mers.Several ways exist to synthesize PLA, however, poly-merization through lactide formation is the most used onindustrial scale, allowing to obtain optimum results interms of mechanical and thermal properties.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f2265567d0d8bf33a5df02c9b37ba66bTest
https://doi.org/10.1002/mame.201000221Test