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.

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 A Window into the Heterogeneity of Human Cerebrospinal Fluid AβPeptides

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Roberta Ghidoni ◽  
Anna Paterlini ◽  
Valentina Albertini ◽  
Elena Stoppani ◽  
Giuliano Binetti ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Basic Research ◽  
Brain Diseases ◽  
Human Cerebrospinal Fluid ◽  
Communication Modes ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain ◽  
Obvious Source

The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβassemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβpeptides. Specifically, we focused our attention on the heterogeneity of the CSF Aβworld discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aβassemblies, and (3) communication modes for Aβpeptides and their microenvironment targets. Finally, we suggest that Aβpeptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function.

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

scholarly journals Extracellular vesicles (exosomes and ectosomes) play key roles in the pathology of brain diseases

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Multiple Sclerosis ◽  
Extracellular Vesicles ◽  
Brain Diseases ◽  
Target Cells ◽  
Surface Binding ◽  
Cells Of Origin ◽  
Relapsing Remitting ◽  
And Function ◽  
The Brain

AbstractLast century, neurons and glial cells were mostly believed to play distinct functions, relevant for the brain. Progressively, however, it became clear that neurons, astrocytes and microglia co-operate intensely with each other by release/binding of signaling factors, direct surface binding and generation/release of extracellular vesicles, the exosomes and ectosomes, called together vesicles in this abstract. The present review is focused on these vesicles, fundamental in various brain diseases. Their properties are extraordinary. The specificity of their membrane governs their fusion with distinct target cells, variable depending on the state and specificity of their cells of origin and target. Result of vesicle fusion is the discharge of their cargos into the cytoplasm of target cells. Cargos are composed of critical molecules, from proteins (various nature and function) to nucleotides (especially miRNAs), playing critical roles in immune and neurodegenerative diseases. Among immune diseases is multiple sclerosis, affected by extensive dysregulation of co-trafficking neural and glial vesicles, with distinct miRNAs inducing severe or reducing effects. The vesicle-dependent differences between progressive and relapsing-remitting forms of the disease are relevant for clinical developments. In Alzheimer’s disease the vesicles can affect the brain by changing their generation and inducing co-release of effective proteins, such Aβ and tau, from neurons and astrocytes. Specific miRNAs can delay the long-term development of the disease. Upon their traffic through the blood-brainbarrier, vesicles of various origin reach fluids where they are essential for the identification of biomarkers, important for diagnostic and therapeutic innovations, critical for the future of many brain patients.

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.

Synaptopathy: dysfunction of synaptic function?

2010 ◽  
Vol 38 (2) ◽  
pp. 443-444 ◽  
Author(s):  
Nils Brose ◽  
Vincent O'Connor ◽  
Paul Skehel
Keyword(s):  
Animal Experimentation ◽  
Structure And Function ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Brain Diseases ◽  
Psychiatric Disease ◽  
Synaptic Dysfunction ◽  
A Value ◽  
Synaptic Structure ◽  
And Function

Synaptopathy is an increasingly popular term used to define key features of neurodegenerative and psychiatric disease. It implies that disruptions in synaptic structure and function are potentially the major determinant of such brain diseases. The Synaptopathies: Dysfunction of Synaptic Function Biochemical Society Focused Meeting brought together several invited speakers, supplemented with short communications from young scientists, who addressed this possibility. The talks spanned the full gamut of approaches that brought molecular, cellular, systems and whole-animal experimentation together to address how fundamental synaptic biology was increasingly informing on dysfunction in disease. The disease and models thereof discussed included Alzheimer's disease, prions, Huntington's disease, Parkinson's disease, schizophrenia and autism. The audience were asked to reflect on whether synaptopathy, although attractive and conceptually useful, provided a significant explanation as the cause of these major diseases. The breadth of the meeting reinforced the complexity of these brain diseases, supported the significance of synaptic dysfunction in disease, but left open the issue as to whether the prime cause of these disorders could be resolved as simple synaptic dysfunction. Thus, despite revealing a value of synaptopathy, further investigation will be required to reveal its balance in the cause and effect in each of the major brain diseases.

Iodide and thiocyanate efflux from brain following injection into rat caudate nucleus

1978 ◽  
Vol 235 (4) ◽  
pp. F331-F337 ◽  
Author(s):  
H. F. Cserr ◽  
B. J. Berman
Keyword(s):  
Caudate Nucleus ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Common Mechanism ◽  
Efflux System ◽  
Guide Cannula ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Loading Estimates ◽  
The Brain

Mechanisms and pathways of 125I and 35SCN efflux from the brain were investigated in anesthetized rats. Tracers were injected into the caudate nucleus through a guide cannula implanted 1 wk previously and concentrations of isotope in brain and cerebrospinal fluid (CSF) were determined at various times after injection. 125I clearance from the brain followed a single exponential curve. In control rats 36.2% of the 125I remained in the brain 30 min after injection and 60.4% in rats pretreated with perchlorate. Comparable values for 35SCN were 25.8% in control rats, 41.0% with perchlorate, and 39.7% with iodide loading. Estimates of 125I and 35SCN effluxes from the brain via the blood-brain barrier and CSF pathways suggest that greater than 95% of efflux crosses the blood-brain barrier. These results indicate that 1)iodide and thiocyanate are transported across the blood-brain barrier by a common mechanism, and 2) this efflux system is an important factor in the control of the distributions of iodide and thiocyanate in the central nervous system.

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