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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.
A stochastic model of ion channel cluster formation in the plasma membrane.
Sato, D, Hernández-Hernández, G, Matsumoto, C, Tajada, S, Moreno, CM, Dixon, RE, O'Dwyer, S, Navedo, MF, Trimmer, JS, Clancy, CE, et al
The Journal of general physiology. 2019;(9):1116-1134
Abstract
Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are "delivered" to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.
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5.
Evaluation of Cerebral Blood Flow Alterations and Acute Neuronal Damage due to Water-Pipe Smoking.
Karakayalı, O, Utku, U, Yılmaz, S
Balkan medical journal. 2019;(2):106-112
Abstract
BACKGROUND Although water-pipe smoking is a great public health problem, data regarding the acute and chronic effects and the degree of toxin exposure are limited. While water pipe-related malignancy, pulmonary, infectious, cardiac effects, infertility, and biological effects have been described in a meta-analysis, there are no studies in the literature about its neurologic effects. AIMS To evaluate water pipe-related acute neurological effects and cerebral blood flow through transcranial Doppler ultrasonography and serum S100 calcium binding protein calcium binding protein level measurements. STUDY DESIGN Prospective observational study. METHODS Vital signs and baseline carboxyhemoglobin and S100 calcium binding protein levels, cerebral flood changes with transcranial Doppler ultrasound were evaluated and recorded before and after water-pipe smoking. RESULTS The mean age of the 31 volunteers was 30.61 (±5.67) years, and 24 of them (77.42%) were male. A statistically significant difference was determined in heart rate, oxygen saturation, systolic and diastolic arterial pressure values before and after water-pipe smoking (p<0.001, p=0.035, p=0.009, p=0.021, respectively). Mean carboxyhemoglobin level was 2.68% (±1.68) before, 14.97% (±4.83) after water-pipe smoking (p<0.001). The S100 calcium binding protein level was 25.05 μ/mL (±8.34) at the beginning, 40.71 μ/mL (±14.06) after water-pipe smoking (p<0.001). An increase was determined in peak, and median middle, anterior and posterior cerebral artery blood flow rates, and a decrease was determined in both the pulsatility index and resistivity index values after water-pipe smoking using transcranial Doppler ultrasound. CONCLUSION Cerebral vasodilation develops due to the increase in cerebral blood flow rate and the decrease in pulsatility index, resistivity index values, and the elevation in carboxyhemoglobin, S100 calcium binding protein level indicates that water-pipe smoking leads to neuronal damage in the acute period.
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6.
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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7.
Polymer microchamber arrays for geometry-controlled drug release: a functional study in human cells of neuronal phenotype.
Kopach, O, Zheng, K, Sindeeva, OA, Gai, M, Sukhorukov, GB, Rusakov, DA
Biomaterials science. 2019;(6):2358-2371
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Abstract
Polyelectrolyte multilayer (PEM) microchambers can provide a versatile cargo delivery system enabling rapid, site-specific drug release on demand. However, experimental evidence for their potential benefits in live human cells is scarce. Equally, practical applications often require substance delivery that is geometrically constrained and highly localized. Here, we establish human-cell biocompatibility and on-demand cargo release properties of the PEM or polylactic acid (PLA)-based microchamber arrays fabricated on a patterned film base. We grow human N2A cells (a neuroblastoma cell line widely used for studies of neurotoxicity) on the surface of the patterned microchamber arrays loaded with either a fluorescent indicator or the ubiquitous excitatory neurotransmitter glutamate. The differentiating human N2A cells show no detrimental effects on viability when growing on either PEM@PLA or PLA-based arrays for up to ten days in vitro. Firstly, we use two-photon (2P) excitation with femtosecond laser pulses to open individual microchambers in a controlled way while monitoring release and diffusion of the fluorescent cargo (rhodamine or FITC fluorescent dye). Secondly, we document the increases in intracellular Ca2+ in local N2A cells in response to the laser-triggered glutamate release from individual microchambers. The functional cell response is site-specific and reproducible on demand and could be replicated by applying glutamate to the cells using a pressurised micropipette. Time-resolved fluorescence imaging confirms the physiological range of the glutamate-evoked intracellular Ca2+ dynamics in the differentiating N2A cells. Our data indicate that the nano-engineering design of the fabricated PEM or PLA-based patterned microchamber arrays could provide a biologically safe and efficient tool for targeted, geometrically constrained drug delivery.
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8.
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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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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10.
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.