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Molecular basis of vitamin D action in neurodegeneration: the story of a team perspective.
Gezen-Ak, D, Dursun, E
Hormones (Athens, Greece). 2019;(1):17-21
Abstract
Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca2+ homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca2+ hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions.
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2.
Why is glycine cleavage system segmentally expressed in radial glia?
Sato, K
Journal of theoretical biology. 2019;:17-19
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3.
Lessons on Differential Neuronal-Death-Vulnerability from Familial Cases of Parkinson's and Alzheimer's Diseases.
Franco, R, Navarro, G, Martínez-Pinilla, E
International journal of molecular sciences. 2019;(13)
Abstract
The main risk of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common neurodegenerative pathologies, is aging. In contrast to sporadic cases, whose symptoms appear at >60 years of age, familial PD or familial AD affects younger individuals. Finding early biological markers of these diseases as well as efficacious treatments for both symptom relief and delaying disease progression are of paramount relevance. Familial early-onset PD/AD are due to genetic factors, sometimes a single mutation in a given gene. Both diseases have neuronal loss and abnormal accumulations of specific proteins in common, but in different brain regions. Despite shared features, the mechanisms underlying the pathophysiological processes are not known. This review aims at finding, among the genetic-associated cases of PD and AD, common trends that could be of interest to discover reliable biomarkers and efficacious therapies, especially those aimed at affording neuroprotection, i.e., the prevention of neuronal death.
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4.
Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K+-Cl- Cotransporter KCC2.
Tillman, L, Zhang, J
BioMed research international. 2019;:8941046
Abstract
Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.
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5.
Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases.
Collin, F
International journal of molecular sciences. 2019;(10)
Abstract
Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of products of lipid, protein and DNA oxidation in vivo. Even if they participate in cell signaling and metabolism regulation, ROS are also formidable weapons against most of the biological materials because of their intrinsic nature. By nature too, neurons are particularly sensitive to oxidation because of their high polyunsaturated fatty acid content, weak antioxidant defense and high oxygen consumption. Thus, the overproduction of ROS in neurons appears as particularly deleterious and the mechanisms involved in oxidative degradation of biomolecules are numerous and complexes. This review highlights the production and regulation of ROS, their chemical properties, both from kinetic and thermodynamic points of view, the links between them, and their implication in neurodegenerative diseases.
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6.
Thalamocortical network: a core structure for integrative multimodal vestibular functions.
Brandt, T, Dieterich, M
Current opinion in neurology. 2019;(1):154-164
Abstract
PURPOSE OF REVIEW To apply the concept of nonreflexive sensorimotor and cognitive vestibular functions and disturbances to the current view of separate right and left thalamocortical systems. RECENT FINDINGS The neuronal modules for sensorimotor and cognitive functions are organized in so-called provincial hubs with intracommunity connections that interact task-dependently via connector hubs. Thalamic subnuclei may serve not only as provincial hubs but also in higher order nuclei as connector hubs. Thus, in addition to its function as a cortical relay station of sensory input, the human thalamus can be seen as an integrative hub for brain networks of higher multisensory vestibular function. Imaging studies on the functional connectivity have revealed a dominance of the right side in right-handers at the upper brainstem and thalamus. A connectivity-based parcellation study has confirmed the asymmetrical organization (i.e., cortical dominance) of the parieto-insular vestibular cortex, an area surrounded by other vestibular cortical areas with symmetrical (nondominant) organization. Notably, imaging techniques have shown that there are no crossings of the vestibular pathways in between the thalamic nuclei complexes. Central vestibular syndromes caused by lesions within the thalamocortical network rarely manifest with rotational vertigo. This can be explained and mathematically simulated by the specific coding of unilateral vestibular dysfunction within different cell systems, the angular velocity cell system (rotational vertigo in lower brainstem lesions) in contrast to the head direction cell system (directional disorientation and swaying vertigo in thalamocortical lesions). SUMMARY The structural and functional separation of the two thalamic nuclei complexes allowed a lateralization of the right and left hemispheric functions to develop. Furthermore, it made possible the simultaneous performance of sensorimotor and cognitive tasks, which require different spatial reference systems in opposite hemispheres, for example, egocentric manipulation of objects (handedness) and allocentric orientation of the self in the environment by the multisensory vestibular system.
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7.
The current status of the magnocellular theory of developmental dyslexia.
Stein, J
Neuropsychologia. 2019;:66-77
Abstract
Some people doubt that the concept of developmental dyslexia (DD) is useful at all because the phonological weaknesses seen in DD cannot be distinguished from those found in every person with poor reading skills, whatever their cause. Here I argue that true DD is characterised by poor temporal processing, hence impaired visual and auditory sequencing, that is caused by impaired development of transient/magnocellular (M-) systems throughout the brain. These deficits can be measured in order to distinguish the causes of the phonological weaknesses in DD from those causing similar deficits in other types of poor reading. Importantly this knowledge can be exploited to develop effective improvements in treatment. The evidence for impaired visual magnocellular function in many, if not all, people with dyslexia is now overwhelming; it is supported not only by psychophysical tests of M- function, but also by electrophysiological, eye movement, attentional, imaging, interventional and genetic findings. Analogously, auditory temporal processing is mediated by auditory transient, 'magnocellular', processing systems, and evidence is accumulating persuasively that this system is also impaired in dyslexics. I briefly introduce the idea that 'motor magnocellular systems' may also be impaired in dyslexia, then consider genetic, immunological and nutritional factors that interact to cause the impaired magnocellular phenotype. I then discuss why the dyslexic phenotype is so common by speculating about what strengths it might confer that would maintain the responsible genes in the human genome.
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8.
Development of the human olfactory system.
Sarnat, HB, Flores-Sarnat, L
Handbook of clinical neurology. 2019;:29-45
Abstract
This chapter focuses on the development of the human olfactory system. In this system, function does not require full neuroanatomical maturity. Thus, discrimination of odorous molecules, including a number within the mother's diet, occurs in amniotic fluid after 28-30 weeks of gestation, at which time the olfactory bulbs are identifiable by MRI. Hypoplasia/aplasia of the bulbs is documented in the third trimester and postnatally. Interestingly, olfactory axons project from the nasal epithelium to the telencephalon before formation of the olfactory bulbs and lack a peripheral ganglion, but the synaptic glomeruli of the future olfactory bulb serves this function. Histologic lamination of the olfactory bulb is present by 14 weeks, but maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the normal transitory fetal ventricular recess. Myelination occurs postnatally. Although olfaction is the only sensory system without direct thalamic projections, the olfactory bulb and anterior olfactory nucleus are, in effect, thalamic surrogates. For example, many dendro-dendritic synapses occur within the bulb between GABAergic granular neurons and periglomerular neurons. Moreover, bulbar synaptic glomeruli are analogous to peripheral ganglia of other sensory cranial nerves. The olfactory tract contains much gray as well as white matter. The olfactory epithelium and bulb both incorporate progenitor cells at all ages. Diverse malformations of the olfactory bulb can be detected by clinical examination, imaging, and neuropathology; indeed, olfactory reflexes of the neonate can be reliably tested. We recommend that such testing be routine in the neonatal neurologic examination, especially in children with brain malformations, endocrinopathies, chromosomopathies, genetic/metabolic disorders, and perinatal hypoxic/ischemic encephalopathy.
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9.
Analysis of neural activity with fluorescent protein biosensors.
Burke, RD, Yaguchi, S
Methods in cell biology. 2019;:519-526
Abstract
Fluorescent calcium sensors provide a means of detecting and analyzing cytoplasmic calcium levels in embryos and larvae. Conventional RNA injection of eggs results in expression of protein sensors throughout larval tissues. Larvae are immobilized for wide field or confocal recordings and video records reveal recurrent fluctuations in cytoplasmic calcium levels in several cell types. Neurons can be identified by location and form, and continuous records made of their activity. Confocal image stacks are registered and Z-axis, fluorescence intensity profiles of individual neurons generated to provide time/activity plots. These optogenetic methods enable analysis in intact larvae of the activity of identified neurons or effectors, such as muscles or ciliary band cells.
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10.
Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons.
Welcome, MO, Mastorakis, NE
Neuromolecular medicine. 2018;(3):281-300
Abstract
The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte-derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed.