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Page 128 of 546-
Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects.
WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.
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[Light and electron microscopic studies of the brain, heart and pancreas in mice infected with MengoM virus].
Infection of ABAF hybride mice with MengoM viruses prepared as a suspension of mouse brain tissue (0.1 ml 10 LD50) after a series of more than 90 animal passages produced a severe panencephalitis and pancreatitis 60 h after inoculation. Histological examinations of the brain, pancreas, and heart revealed damage to the central nervous system and the acinar cells of the pancreas, consisting of a degeneration of the specific cells and their organelles, with little involvement of the heart muscle cells detectable with the electron microscope. This was consistent with high virus titers in the tissues in the period immediately following infection. The acute damage of exocrine tissues was without evidence of diabetes-like changes in the islets of Langerhans.
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Mapping the hotspots for DNA repair synthesis in human brain organoids.
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Out of the Cave, Into the Light? Modeling Mental Illness With Organoids.
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[The contribution of cerebral organoids to the understanding and treatment of rare genetic diseases with neurodevelopmental disorders].
Rare genetic diseases with neurodevelopmental disorders (NDDs) encompass several heterogeneous conditions (autism spectrum disorder (ASD), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), specific learning disorder (SLD), among others). Currently, few treatments are available for these patients. The difficulty in accessing human brain samples and the discrepancies between human and animal models highlight the need for new research approaches. One promising approach is the use of the cerebral organoids. These 3D, self-organized structures, generated from induced pluripotent stem cells (iPSCs), enable the reproduction of the stages of human brain development, from the proliferation of neural stem cells to their differentiation into neurons, oligodentrocytes, and astrocytes. Cerebral organoids hold great promise in understanding brain development and in the search for treatments.
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From enhanceropathies to the epigenetic manifold underlying human cognition.
A vast portion of intellectual disability and autism spectrum disorders is genetically caused by mutations in chromatin modulators. These proteins play key roles in development and are also highly expressed in the adult brain. Specifically, the pivotal role of chromatin regulation in transcription has placed enhancers at the core of neurodevelopmental disorders (NDDs) studies, ushering in the coining of the term enhanceropathies. The convergence of these disorders is multilayered, spanning from molecular causes to pathophysiological traits, including extensive overlaps between enhanceropathies and neurocristopathies. The reconstruction of epigenetic circuitries wiring development and underlying cognitive functions has gone hand in hand with the development of tools that increase the sensitivity of identifying regulatory regions and linking enhancers to their target genes. The available models, including loop extrusion and phase separation, have been bringing into relief complementary aspects to interpret gene regulation datasets, reinforcing the idea that enhancers are not all the same and that regulatory regions possess shades of enhancer-ness and promoter-ness. The current limits in enhancer definition, within the emerging broader understanding of chromatin dynamics in time and space, are now on the verge of being transformed by the possibility to interrogate developmentally relevant three-dimensional cellular models at single-cell resolution. Here we discuss the contours of how these technological advances, as well as the epistemic limitations they are set to overcome, may well usher in a change of paradigm for NDDs, moving the quest for convergence from enhancers to the four-dimensional (4D) genome.
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Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids.
Brain organoids are promising tools for disease modeling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here, we report the directed self-organization of human induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network at a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons with supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed GABA polarity switch and reduced GDPs in >40 day BENO indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months and evidence for long-term potentiation. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modeling of disease.
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Molecular Features of the Measles Virus Viral Fusion Complex That Favor Infection and Spread in the Brain.
Measles virus (MeV) bearing a single amino acid change in the fusion protein (F)-L454W-was isolated from two patients who died of MeV central nervous system (CNS) infection. This mutation in F confers an advantage over wild-type virus in the CNS, contributing to disease in these patients. Using murine ex vivo organotypic brain cultures and human induced pluripotent stem cell-derived brain organoids, we show that CNS adaptive mutations in F enhance the spread of virus ex vivo. The spread of virus in human brain organoids is blocked by an inhibitory peptide that targets F, confirming that dissemination in the brain tissue is attributable to F. A single mutation in MeV F thus alters the fusion complex to render MeV more neuropathogenic. IMPORTANCE Measles virus (MeV) infection can cause serious complications in immunocompromised individuals, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE), another severe central nervous system (CNS) complication, develop even in the face of a systemic immune response. Both MIBE and SSPE are relatively rare but lethal. It is unclear how MeV causes CNS infection. We introduced specific mutations that are found in MIBE or SSPE cases into the MeV fusion protein to test the hypothesis that dysregulation of the viral fusion complex-comprising F and the receptor binding protein, H-allows virus to spread in the CNS. Using metagenomic, structural, and biochemical approaches, we demonstrate that altered fusion properties of the MeV H-F fusion complex permit MeV to spread in brain tissue.
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Submicroscopic changes of cortical capillary pericytes in human perifocal brain edema.
Human brain capillary pericytes were studied by electron microscopy. Cortical biopsies from 17 patients with brain edema associated to brain trauma, tumors and congenital malformations were analysed. The data obtained in this study showed that pericytes like endothelial cells exhibited remarkable edematous changes, increased vacuolar and vesicular transport, formation of transient transpericytal channels and tubular structures, demonstrating pericyte brain barrier dysfunction. Images of normal and contracted pericytes showing shallow and deep nuclear invaginations, nuclear basal lamina, actin and myosin-like filaments and coupled interaction with endothelial cells through macula occludens were also encountered. Some pericytes displayed hypertrophic and necrotic changes. Phagocytic pericytes exhibited ingested erythrocytes. Hypertrophic pericytes inducing basement membrane splitting and degenerated pericytes with lacunar enlargement of endoplasmic reticulum, deposit of dense osmiophilic bodies and glycogen granules, vacuolization, hydropic changes of Golgi apparatus, and pleomorphic mitochondria were also found. Certain micropinocytotic vesicles seem to be orientated to multivesicular bodies suggesting that pericytes might play some role in edema resolution. Evidence of pericyte transformation into microglial cells or division into phagocytic cells and pericyte migration were not found.
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Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays.
Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.