scholarly journals Ngly1 −/− rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems

2020 ◽  
Vol 29 (10) ◽  
pp. 1635-1647 ◽  
Author(s):  
Makoto Asahina ◽  
Reiko Fujinawa ◽  
Sayuri Nakamura ◽  
Kotaro Yokoyama ◽  
Ryuichi Tozawa ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Human Subjects ◽  
Significant Loss ◽  
Ubiquitinated Proteins ◽  
Central Nervous Systems ◽  
Mature Neurons ◽  
The Central Nervous System ◽  
Axonal Degradation ◽  
Lateral Nucleus ◽  
Disability Movement

Abstract N-glycanase 1 (NGLY1) deficiency, an autosomal recessive disease caused by mutations in the NGLY1 gene, is characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, movement disorders and other neurological phenotypes. Because of few animal models that recapitulate these clinical signatures, the mechanisms of the onset of the disease and its progression are poorly understood, and the development of therapies is hindered. In this study, we generated the systemic Ngly1-deficient rodent model, Ngly1−/− rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. These phenotypes in Ngly1−/− rats are consistent with symptoms in human patients. In accordance with the pivotal role played by NGLY1 in endoplasmic reticulum-associated degradation processes, cleaving N-glycans from misfolded glycoproteins in the cytosol before they can be degraded by the proteasome, loss of Ngly1 led to accumulation of cytoplasmic ubiquitinated proteins, a marker of misfolded proteins in the neurons of the central nervous system of Ngly1−/− rats. Histological analysis identified prominent pathological abnormalities, including necrotic lesions, mineralization, intra- and extracellular eosinophilic bodies, astrogliosis, microgliosis and significant loss of mature neurons in the thalamic lateral and the medial parts of the ventral posterior nucleus and ventral lateral nucleus of Ngly1−/− rats. Axonal degradation in the sciatic nerves was also observed, as in human subjects. Ngly1−/− rats, which mimic the symptoms of human patients, will be a useful animal model for preclinical testing of therapeutic options and understanding the detailed mechanisms of NGLY1 deficiency.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals Transient activation of the Notch-her15.1 axis plays an important role in the maturation of V2b interneurons

Development ◽  
2020 ◽  
Vol 147 (16) ◽  
pp. dev191312
Author(s):  
Takamasa Mizoguchi ◽  
Michi Fukada ◽  
Miku Iihama ◽  
Xuehui Song ◽  
Shun Fukagawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Notch Signaling ◽  
Axon Growth ◽  
Gabaergic Neurons ◽  
Axonal Outgrowth ◽  
Fate Determination ◽  
Transient Activation ◽  
Mature Neurons ◽  
The Central Nervous System ◽  
Signaling Activation

ABSTRACTIn the vertebrate ventral spinal cord, p2 progenitors give rise to two interneuron subtypes: excitatory V2a interneurons and inhibitory V2b interneurons. In the differentiation of V2a and V2b cells, Notch signaling promotes V2b fate at the expense of V2a fate. Later, V2b cells extend axons along the ipsilateral side of the spinal cord and express the inhibitory transmitter GABA. Notch signaling has been reported to inhibit the axonal outgrowth of mature neurons of the central nervous system; however, it remains unknown how Notch signaling modulates V2b neurite outgrowth and maturation into GABAergic neurons. Here, we have investigated neuron-specific Notch functions regarding V2b axon growth and maturation into zebrafish GABAergic neurons. We found that continuous neuron-specific Notch activation enhanced V2b fate determination but inhibited V2b axonal outgrowth and maturation into GABAergic neurons. These results suggest that Notch signaling activation is required for V2b fate determination, whereas its downregulation at a later stage is essential for V2b maturation. Accordingly, we found that a Notch signaling downstream gene, her15.1, showed biased expression in V2 linage cells and downregulated expression during the maturation of V2b cells, and continuous expression of her15.1 repressed V2b axogenesis. Our data suggest that spatiotemporal control of Notch signaling activity is required for V2b fate determination, maturation and axogenesis.

Malformation of the Brain, Skull, and Spine

2021 ◽  
pp. 1057-1070
Author(s):  
Lily C. Wong-Kisiel
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Developmental Delay ◽  
Abnormal Development ◽  
Gene Expressions ◽  
Common Cause ◽  
Genetic Causes ◽  
The Central Nervous System ◽  
The Brain ◽  
Central Nervous System Malformation

Abnormal development of the central nervous system is a common cause of developmental delay and epilepsy. An understanding of central nervous system malformation begins with an overview of normal embryology. Genetic advances in embryogenesis have unfolded a complex orchestration of gene expressions in place of the traditional developmental epochs (induction, neurulation, proliferation, migration, organization, synaptogenesis, and myelination). Causes of malformation of the central nervous system are multifactorial. Genetic causes, vitamin excess or deficiency, infections, or teratogens any time during pregnancy may disturb the preprogrammed mechanisms.

The Development of a Human Gait Model With Predictive Capability and the Simulation of Able-Bodied Gait

2015 ◽  
Author(s):  
Jinming Sun ◽  
Shaoli Wu ◽  
Philip A. Voglewede
Keyword(s):  
Control Algorithm ◽  
Human Subjects ◽  
Human Gait ◽  
Control Input ◽  
Trial And Error ◽  
Predictive Capability ◽  
Gait Simulation ◽  
Plant Model ◽  
The Central Nervous System ◽  
The Cost

The development of current prostheses and orthoses typically follows a trial and error approach where the devices are designed based on experience, tried on human subjects and then redesigned iteratively. This design approach is costly, risky and time consuming. A predictive human gait model is desired such that prostheses can be virtually tested so that their performance can be predicted qualitatively, the cost can be reduced, and the risks can be minimized. The development of such a model is explained in this paper. The developed model includes two parts: a plant model which represents the forward dynamics of human gait and a controller which represents the central nervous system (CNS). The development of the plant model is explained in a different paper. This paper focuses on the control algorithm development and able-bodied gait simulation. The controller proposed in this paper utilizes model predictive control (MPC). MPC uses an internal model to predict the output in advance, compare the predicted output to the reference, and optimize control input so that the error between them is minimal. The developed predictive human gait model was validated by simulating able-bodied human gait. The simulation results showed that the controller is able to simulate the kinematic output close to experimental data.

scholarly journals Mechanisms of spreading depolarization in vertebrate and insect central nervous systems

2016 ◽  
Vol 116 (3) ◽  
pp. 1117-1127 ◽  
Author(s):  
Kristin E. Spong ◽  
R. David Andrew ◽  
R. Meldrum Robertson
Keyword(s):  
Locusta Migratoria ◽  
Model Systems ◽  
Control Mechanisms ◽  
Cellular Mechanisms ◽  
Nervous Systems ◽  
Spreading Depolarization ◽  
Metathoracic Ganglion ◽  
Evolutionarily Conserved ◽  
Central Nervous Systems ◽  
The Central Nervous System

Spreading depolarization (SD) is generated in the central nervous systems of both vertebrates and invertebrates. SD manifests as a propagating wave of electrical depression caused by a massive redistribution of ions. Mammalian SD underlies a continuum of human pathologies from migraine to stroke damage, whereas insect SD is associated with environmental stress-induced neural shutdown. The general cellular mechanisms underlying SD seem to be evolutionarily conserved throughout the animal kingdom. In particular, SD in the central nervous system of Locusta migratoria and Drosophila melanogaster has all the hallmarks of mammalian SD. Locust SD is easily induced and monitored within the metathoracic ganglion (MTG) and can be modulated both pharmacologically and by preconditioning treatments. The finding that the fly brain supports repetitive waves of SD is relatively recent but noteworthy, since it provides a genetically tractable model system. Due to the human suffering caused by SD manifestations, elucidating control mechanisms that could ultimately attenuate brain susceptibility is essential. Here we review mechanisms of SD focusing on the similarities between mammalian and insect systems. Additionally we discuss advantages of using invertebrate model systems and propose insect SD as a valuable model for providing new insights to mammalian SD.

scholarly journals Status of Brain Imaging in Gastroparesis

2020 ◽  
Vol 2 (2) ◽  
pp. 58-70
Author(s):  
Zorisadday Gonzalez ◽  
Richard W. McCallum
Keyword(s):  
Brain Imaging ◽  
Treatment Strategies ◽  
Nausea And Vomiting ◽  
Reflex Response ◽  
Current Status ◽  
Brain Circuits ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
The Brain ◽  
Neuroimaging Techniques

The pathophysiology of nausea and vomiting in gastroparesis is complicated and multifaceted involving the collaboration of both the peripheral and central nervous systems. Most treatment strategies and studies performed in gastroparesis have focused largely on the peripheral effects of this disease, while our understanding of the central nervous system mechanisms of nausea in this entity is still evolving. The ability to view the brain with different neuroimaging techniques has enabled significant advances in our understanding of the central emetic reflex response. However, not enough studies have been performed to further explore the brain–gut mechanisms involved in nausea and vomiting in patients with gastroparesis. The purpose of this review article is to assess the current status of brain imaging and summarize the theories about our present understanding on the central mechanisms involved in nausea and vomiting (N/V) in patients with gastroparesis. Gaining a better understanding of the complex brain circuits involved in the pathogenesis of gastroparesis will allow for the development of better antiemetic prophylactic and treatment strategies.

scholarly journals Impact of Exercise on Immunometabolism in Multiple Sclerosis

2020 ◽  
Vol 9 (9) ◽  
pp. 3038 ◽  
Author(s):  
Remsha Afzal ◽  
Jennifer K Dowling ◽  
Claire E McCoy
Keyword(s):  
Multiple Sclerosis ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Benefits ◽  
Demyelinating Lesions ◽  
Inflammatory State ◽  
Autoimmune Condition ◽  
The Central Nervous System ◽  
Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

The Development of Pneumostrongylus tenuis in the Central Nervous System of White-tailed Deer

1965 ◽  
Vol 2 (4) ◽  
pp. 360-379 ◽  
Author(s):  
Roy C. Anderson
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Medulla Oblongata ◽  
Grey Matter ◽  
Plasma Cells ◽  
Central Canal ◽  
Surrounding Tissue ◽  
Parasite Relationship ◽  
Central Nervous Systems ◽  
The Central Nervous System

The central nervous systems of five fawns (Odocoileus virginianus borealis), infected experimentally with Pneumostrongylus tenuis, were studied histologically 10, 20, 25, 30, and 40 days after infection. In the 10–30 day fawns young developing worms were found in dorsal horns of the grey matter of all regions of the spinal cord. A few worms were found in white matter and in the medulla oblongata. In the fawn autopsied 40 days after infection all but one of about 25 worms found were in the subdural space. Worms in the grey matter usually lay in cell-free tunnels surrounded by compressed neural tissue. There was little reaction of, or cellular infiltration in, surrounding tissue. Malacia was absent in all parts of grey matter. The central canal was normal and the brain, other than the medulla oblongata, was not involved. In the white matter, scattered single myelin sheath degeneration as well as degeneration and disappearance of axis cylinders were common. Occasionally there were tiny malacic areas in white matter, especially near worms. Infiltrations of eosinophils, lymphocytes, and plasma cells were commonly observed in and on the dura mater, the epineurium, ganglion capsules, and other tissues of the epidural space. The relative dearth of histopathologic findings helps to explain the rarity and slightness of neurologic signs in infected fawns and is indicative perhaps of a long and well established host-parasite relationship. This is in contrast to the situation in moose (Alces a. americana) where severe traumatic damage to the spinal cord by P. tenuis is associated with ataxia and paralysis.

Features of molecule expression markers of insulin resistance in experimental Alzheimer’s disease

2015 ◽  
Vol 61 (4) ◽  
pp. 43-48
Author(s):  
Ya V Gorina ◽  
Yu K Komleva ◽  
O L Lopatina ◽  
V V Volkova ◽  
G E Gersog ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Molecular Markers ◽  
Molecular Mechanisms ◽  
Cognitive Disorders ◽  
Brain Regions ◽  
Significant Loss ◽  
Amyloid Accumulation ◽  
The Central Nervous System

Alzheimer’s Disease (AD) is characterized by a significant loss of neurons and synapses, especially in the hippocampus and cortex, the extracellular β-amyloid accumulation and formation of neurofibrillary tangles. Insulin resistance plays important role in neurodegeneration and cognitive disorders in the central nervous system, especially AD. However, the cellular and molecular mechanisms that connect insulin resistance and Alzheimer’s pathogenesis remain largely unexplained. Therefore, great importance is the identification of molecular markers that allow to define new approaches to targeted pharmacological correction of neurodegeneration. This article describes the study of the expression of molecular markers, namely, IRAP, GLUT4, and IL-18 in different brain regions (hippocampus, olfactory bulb) rats with experimental AD

scholarly journals A comparative analysis of neural taste processing in animals

2011 ◽  
Vol 366 (1574) ◽  
pp. 2171-2180 ◽  
Author(s):  
Gabriela de Brito Sanchez ◽  
Martin Giurfa
Keyword(s):  
Nervous System ◽  
Limited Range ◽  
Taste Perception ◽  
Gustatory Receptor ◽  
Central Processing ◽  
Pattern Processing ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
Taste Processing ◽  
Fibre Pattern

Understanding taste processing in the nervous system is a fundamental challenge of modern neuroscience. Recent research on the neural bases of taste coding in invertebrates and vertebrates allows discussion of whether labelled-line or across-fibre pattern encoding applies to taste perception. While the former posits that each gustatory receptor responds to one stimulus or a very limited range of stimuli and sends a direct ‘line’ to the central nervous system to communicate taste information, the latter postulates that each gustatory receptor responds to a wider range of stimuli so that the entire population of taste-responsive neurons participates in the taste code. Tastes are represented in the brain of the fruitfly and of the rat by spatial patterns of neural activity containing both distinct and overlapping regions, which are in accord with both labelled-line and across-fibre pattern processing of taste, respectively. In both animal models, taste representations seem to relate to the hedonic value of the tastant (e.g. palatable versus non-palatable). Thus, although the labelled-line hypothesis can account for peripheral taste processing, central processing remains either unknown or differs from a pure labelled-line coding. The essential task for a neuroscience of taste is, therefore, to determine the connectivity of taste-processing circuits in central nervous systems. Such connectivity may determine coding strategies that differ significantly from both the labelled-line and the across-fibre pattern models.

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