scholarly journals SUMOylation and calcium signalling: potential roles in the brain and beyond

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Leticia Coelho-Silva ◽  
Gary J. Stephens ◽  
Helena Cimarosti
Keyword(s):  
Protein Modification ◽  
Calcium Signalling ◽  
Cellular Functions ◽  
Normal Functioning ◽  
Sumo Conjugation ◽  
The Central Nervous System ◽  
Cardiac System ◽  
And Function ◽  
The Brain ◽  
Ca2 Channels

Small ubiquitin-like modifier (SUMO) conjugation (or SUMOylation) is a post-translational protein modification implicated in alterations to protein expression, localization and function. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Calcium ion (Ca2+) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascular diseases. Intracellular Ca2+ levels are tightly regulated; at rest, most Ca2+ is retained in organelles, such as the sarcoplasmic reticulum, or in the extracellular space, whereas depolarization triggers a series of events leading to Ca2+ entry, followed by extrusion and reuptake. The mechanisms that maintain Ca2+ homoeostasis are candidates for modulation at the post-translational level. Here, we review the effects of protein SUMOylation, including Ca2+ channels, their proteome and other proteins associated with Ca2+ signalling, on vital cellular functions, such as neurotransmission within the central nervous system (CNS) and in additional systems, most prominently here, in the cardiac system.

scholarly journals JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2190
Author(s):  
Clara Alice Musi ◽  
Graziella Agrò ◽  
Francesco Santarella ◽  
Erika Iervasi ◽  
Tiziana Borsello
Keyword(s):  
Brain Diseases ◽  
Synaptic Dysfunction ◽  
Common Mechanism ◽  
Cellular Functions ◽  
Prodromal Phase ◽  
Aβ Oligomers ◽  
Disease Biomarker ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain

The c-Jun N-terminal kinase 3 (JNK3) is the JNK isoform mainly expressed in the brain. It is the most responsive to many stress stimuli in the central nervous system from ischemia to Aβ oligomers toxicity. JNK3 activity is spatial and temporal organized by its scaffold protein, in particular JIP-1 and β-arrestin-2, which play a crucial role in regulating different cellular functions in different cellular districts. Extensive evidence has highlighted the possibility of exploiting these adaptors to interfere with JNK3 signaling in order to block its action. JNK plays a key role in the first neurodegenerative event, the perturbation of physiological synapse structure and function, known as synaptic dysfunction. Importantly, this is a common mechanism in many different brain pathologies. Synaptic dysfunction and spine loss have been reported to be pharmacologically reversible, opening new therapeutic directions in brain diseases. Being JNK3-detectable at the peripheral level, it could be used as a disease biomarker with the ultimate aim of allowing an early diagnosis of neurodegenerative and neurodevelopment diseases in a still prodromal phase.

Ventricular and Cerebrospinal Fluid System

2017 ◽  
pp. 409-434
Author(s):  
Eduardo E. Benarroch ◽  
Jeremy K. Cutsforth-Gregory ◽  
Kelly D. Flemming
Keyword(s):  
Cerebrospinal Fluid ◽  
Neural Tissue ◽  
Local Environment ◽  
System P ◽  
Neurologic Disorders ◽  
Unique System ◽  
The Central Nervous System ◽  
Protective Structures ◽  
And Function ◽  
The Brain

The meninges, ventricular system, subarachnoid space, and cerebrospinal fluid (CSF) constitute a functionally unique system that has an important role in maintaining a stable environment within which the central nervous system can function. The membranes that constitute the meninges serve as supportive and protective structures for neural tissue. The CSF itself provides a cushioning effect during rapid movement of the head and mechanical buoyancy to the brain. In addition to providing a pathway for the removal of brain metabolites, it functions as a chemical reservoir that protects the local environment of the brain from changes that may occur in the blood, thus ensuring the brain’s continued undisturbed performance. The CSF system is present at the supratentorial, posterior fossa, and spinal levels. Because of this extensive anatomical distribution and function, pathologic alterations of the CSF system can occur in many neurologic disorders.

scholarly journals Environmental and Nutritional “Stressors” and Oligodendrocyte Dysfunction: Role of Mitochondrial and Endoplasmatic Reticulum Impairment

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 553
Author(s):  
Jessica Maiuolo ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
Saverio Nucera ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Energy Production ◽  
Lipid Synthesis ◽  
Main Function ◽  
Cellular Functions ◽  
Mitochondrial Oxidative Stress ◽  
The Central Nervous System ◽  
Altered Regulation ◽  
The Brain

Oligodendrocytes are myelinating cells of the central nervous system which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, insulating them and facilitating nerve conduction through saltatory propagation. The myelination process requires the consumption a large amount of energy and a high metabolic turnover. Mitochondria are essential organelles which regulate many cellular functions, including energy production through oxidative phosphorylation. Any mitochondrial dysfunction impacts cellular metabolism and negatively affects the health of the organism. If the functioning of the mitochondria is unbalanced, the myelination process is impaired. When myelination has finished, oligodendrocyte will have synthesized about 40% of the total lipids present in the brain. Since lipid synthesis occurs in the cellular endoplasmic reticulum, the dysfunction of this organelle can lead to partial or deficient myelination, triggering numerous neurodegenerative diseases. In this review, the induced malfunction of oligodendrocytes by harmful exogenous stimuli has been outlined. In particular, the effects of alcohol consumption and heavy metal intake are discussed. Furthermore, the response of the oligodendrocyte to excessive mitochondrial oxidative stress and to the altered regulation of the functioning of the endoplasmic reticulum will be explored.

scholarly journals The Role of Adrenoceptors in the Retina

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2594
Author(s):  
Yue Ruan ◽  
Tobias Böhmer ◽  
Subao Jiang ◽  
Adrian Gericke
Keyword(s):  
Visual Information ◽  
Vision Loss ◽  
Retinal Diseases ◽  
System A ◽  
The Central Nervous System ◽  
The Individual ◽  
And Function ◽  
The Brain

The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha1 (α1)-, alpha2 (α2)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases.

scholarly journals A sart1 Zebrafish Mutant Results in Developmental Defects in the Central Nervous System

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Hannah E. Henson ◽  
Michael R. Taylor
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Developmental Defects ◽  
Whole Exome ◽  
The Central Nervous System ◽  
And Function ◽  
Upregulated Genes ◽  
The Brain

The spliceosome consists of accessory proteins and small nuclear ribonucleoproteins (snRNPs) that remove introns from RNA. As splicing defects are associated with degenerative conditions, a better understanding of spliceosome formation and function is essential. We provide insight into the role of a spliceosome protein U4/U6.U5 tri-snRNP-associated protein 1, or Squamous cell carcinoma antigen recognized by T-cells (Sart1). Sart1 recruits the U4.U6/U5 tri-snRNP complex to nuclear RNA. The complex then associates with U1 and U2 snRNPs to form the spliceosome. A forward genetic screen identifying defects in choroid plexus development and whole-exome sequencing (WES) identified a point mutation in exon 12 of sart1 in Danio rerio (zebrafish). This mutation caused an up-regulation of sart1. Using RNA-Seq analysis, we identified additional upregulated genes, including those involved in apoptosis. We also observed increased activated caspase 3 in the brain and eye and down-regulation of vision-related genes. Although splicing occurs in numerous cells types, sart1 expression in zebrafish was restricted to the brain. By identifying sart1 expression in the brain and cell death within the central nervous system (CNS), we provide additional insights into the role of sart1 in specific tissues. We also characterized sart1’s involvement in cell death and vision-related pathways.

scholarly journals Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma

2019 ◽  
Vol 116 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
Gregor Hutter ◽  
Johanna Theruvath ◽  
Claus Moritz Graef ◽  
Michael Zhang ◽  
Matthew Kenneth Schoen ◽  
...  
Keyword(s):  
Fatal Outcome ◽  
Tumor Formation ◽  
Tumor Associated Macrophages ◽  
Effector Cells ◽  
Promising Target ◽  
Signaling Axis ◽  
Transcriptional Changes ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain

Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2RFP) and microglia (Cx3cr1GFP). We show that even in the absence of phagocytizing macrophages (Ccr2RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.

scholarly journals Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Sylwia Owczarek ◽  
Marie Louise Bang ◽  
Vladimir Berezin
Keyword(s):  
Central Nervous System ◽  
Cell Adhesion Molecules ◽  
Synaptic Membranes ◽  
Dependent Manner ◽  
Related Protein ◽  
Synaptic Complex ◽  
The Central Nervous System ◽  
And Function ◽  
Activity Dependent ◽  
The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

scholarly journals Autoregulation of the Brain Temperature during Whole Body Hyperthermia

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Haim I. Bicher ◽  
Nodar Mitagvaria ◽  
Marina Devdariani ◽  
Lia Davlianidze ◽  
Marina Nebieridze ◽  
...  
Keyword(s):  
Blood Circulation ◽  
Oxygen Supply ◽  
Brain Temperature ◽  
Whole Body ◽  
Normal Functioning ◽  
Temperature Changes ◽  
Whole Body Hyperthermia ◽  
Upper Limit ◽  
The Central Nervous System ◽  
The Brain

The aim of this study was revealing the temperature changes in rats' brain tissue caused by whole body hyperthermia. The analysis of received results allows to conclude that the brain has a highly secured system of temperature autoregulation against the exogenous temperature changes. The upper limit of this autoregulation (for rats, at least) is in the range of 45°C of environment. An important role in the normal functioning of the brain temperature autoregulation system belongs to Nitric Oxide. The behavioral disorders, observed in animals after whole body hyperthermia (sure within the range of brain temperature autoregulation) are hardly associated with the changes in temperature of the Central Nervous System, but rather have to be mediated by impaired blood circulation and oxygen supply to the brain tissues, caused by the rapid deterioration of the blood rheological properties.

scholarly journals Blood-Brain Barrier Overview: Structural and Functional Correlation

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Abeer Alahmari
Keyword(s):  
Blood Brain Barrier ◽  
Extracellular Fluid ◽  
Vital Role ◽  
Brain Barrier ◽  
Comprehensive Overview ◽  
Functional Correlation ◽  
Blood Brain ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain

The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain’s extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.

scholarly journals Repression of lysosomal transcription factors Tfeb and Tfe3 is essential for the development and function of microglia

2020 ◽  
Author(s):  
Harini Iyer ◽  
Kimberle Shen ◽  
Ana M. Meireles ◽  
William S. Talbot
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gtpase Activating Protein ◽  
Phagocytic Cells ◽  
Lysosomal Activity ◽  
Regulatory Circuit ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain ◽  
Macrophage Lineage

SUMMARYAs the primary phagocytic cells of the central nervous system, microglia exquisitely regulate their lysosomal activity to facilitate brain development and homeostasis. However, mechanisms that coordinate lysosomal activity with microglia development, migration, and function remain unclear. Here we show that embryonic macrophages require the lysosomal GTPase RagA and the GTPase-activating protein Folliculin (Flcn) for colonization of the brain. Mutants lacking RagA and Flcn have nearly identical phenotypes, suggesting that RagA and Flcn act in concert in developing microglia. Furthermore, we demonstrate that RagA and Flcn repress the key lysosomal transcription factor Tfeb, and its homologs Tfe3a and Tfe3b, in macrophages. Accordingly, defects in rraga mutants can be restored by simultaneous mutations in tfeb, tfe3a, and tfe3b, and overexpression of tfe3b in the macrophage lineage recapitulates the major defects observed in rraga and flcn mutants. Collectively, our data define a lysosomal regulatory circuit that is essential for early development of microglia.

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