Peroxisome Biology: Experimental Models, Peroxisomal Disorders and Neurological Diseases

2020 ◽  
Keyword(s):  
Neurological Diseases ◽  
Experimental Models ◽  
Peroxisomal Disorders

scholarly journals Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

2020 ◽  
Vol 21 (10) ◽  
pp. 3575 ◽  
Author(s):  
Viviana di Giacomo ◽  
Annalisa Chiavaroli ◽  
Lucia Recinella ◽  
Giustino Orlando ◽  
Amelia Cataldi ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Cannabis Sativa ◽  
Ex Vivo ◽  
Neurological Diseases ◽  
Docking Studies ◽  
Experimental Models ◽  
Neuroprotective Effects ◽  
Rat Astrocytes ◽  
Species Production

Cannabidiol (CBD) and cannabigerol (CBG) are Cannabis sativa terpenophenols. Although CBD’s effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases. Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K+ 60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed. Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor. Conclusion: The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.

Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications

2019 ◽  
Vol 26 (2) ◽  
pp. 170-184
Author(s):  
Wei Zhou ◽  
Dongrui Ma ◽  
Eng-King Tan
Keyword(s):  
Neurological Disorders ◽  
Neurological Diseases ◽  
Mitochondrial Gene ◽  
Experimental Models ◽  
Loss Of Function ◽  
Motor Neuron Diseases ◽  
Therapeutic Implications ◽  
Mitochondrial Inner Membrane ◽  
Mitochondrial Defects ◽  
Neurological Conditions

CHCHD2 mutations have been identified in various neurological diseases such as Parkinson’s disease (PD), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). It is also the first mitochondrial gene whose mutations lead to PD. CHCHD10 is a homolog of CHCHD2; similar to CHCHD2, various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD and AD, with a high frequency of CHCHD10 mutations found in motor neuron diseases. Functionally, CHCHD2 and CHCHD10 have been demonstrated to interact with each other in mitochondria. Recent studies link the biological functions of CHCHD2 to the MICOS complex (mitochondrial inner membrane organizing system). Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 and CHCHD10 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects. Strategies to maintain or enhance mitochondria cristae could provide opportunities to correct the associated cellular defects in disease state and unravel potential novel targets for CHCHD2-linked neurological conditions.

scholarly journals Probing the Dynamics of Neuronal Proteins In Vivo Using Non-Canonical Amino Acids Tagging

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Kevin P. Lin ◽  
Aya M. Saleh ◽  
Kathryn R. Jacobson ◽  
Sarah Calve ◽  
Tamara L. Kinzer-Ursem
Keyword(s):  
Neurological Disorders ◽  
Temporal Dynamics ◽  
Click Reaction ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Selective Enrichment ◽  
Neuronal Proteins ◽  
Canonical Amino Acid ◽  
Brain Tissues

Background and Hypothesis: More than 600 neurological disorders have been identified, each with varying degrees of complexity and level of molecular understanding. However, current approaches are inadequate to capture the complex progressive nature of most neurological diseases. Therefore, developing techniques capable of probing the temporal dynamics of neuronal proteins in rodents, the most commonly used experimental models, is imperative for proper understanding of mechanisms driving neurological disorders. In this project, a protein labeling technique that enables selective labeling of newly synthesized proteins in vivo is utilized. In this technique, the non-canonical amino acid azidohomoalanine (AHA) is injected into mice to achieve global proteome labeling. AHA is an azide-tagged methionine (Met) analog that is incorporated into the nascent proteins using endogenous translational mechanisms. The azide functional group of AHA allows selective enrichment of the newly synthesized proteins from brain tissues via click-chemistry using alkynebearing affinity tags. This will be followed by detecting the AHA-labeled protein using mass spectrometry. We hypothesize that this labeling technique will help map the dynamics of the brain proteome in health and disease. This will ultimately provide insights into mechanisms underlying complex neurological diseases. Experimental Design or Project Methods: C57Bl/6 murine dams were injected with 0.1 mg/g AHA for two days. Brain tissues were harvested, homogenized and lysates were reacted with biotin-alkyne using copper-catalyzed click reaction. Biotinylated proteins were then enriched using NeutrAvidin beads and eluted by boiling in 2% SDS. Results: Tissues were fractionated into different subcellular components (cytosolic, nuclear, membrane, cytoskeletal, and extracellular matrix) using buffers of different stringency. Western blot analysis of clicked tissues using Streptavidin-fluorophore indicated effective incorporation of AHA into different cellular fractions of brain tissues. Additionally, the analysis of eluted proteins revealed successful enrichment and elution of AHA-labeled proteins. Conclusion and Potential Impact: Successful incorporation of AHA in nascent neuronal proteins can lead to a comprehensive quantitative approach for elucidating changes in the regulation of neuronal proteins in disease states.

scholarly journals Influence of Striatal Astrocyte Dysfunction on Locomotor Activity in Dopamine-depleted Rats

2021 ◽  
Author(s):  
Dmitry Voronkov ◽  
◽  
Alla Stavrovskaya ◽  
Artem Olshanskiy ◽  
Anastasia Guschina ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Neuronal Degeneration ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Immunohistochemical Localization ◽  
Motor Dysfunction ◽  
Nigrostriatal System ◽  
Control Group ◽  
Dopamine Depletion ◽  
The Right

Introduction: Astrocyte dysfunction is the common pathology resulting in failure of astrocyte-neuron interaction in neurological diseases, including Parkinson’s Disease (PD). To date, only few experimental models of selective ablation of astrocytes are known. The aim of present study was to evaluate the effect of striatal injections of selective glial toxin L-aminoadipic acid (L-AA) on the locomotor activity in L-AA-treated catecholamine-depleted animals and in L-AA-treated saline-injected rats. Materials and Methods. Wistar rats (n=12) were stereotaxically, unilaterally injected with L-AA (100 µg in 5 µl phosphate buffered saline) into the right striatum. Control, sham-operated rats (n=12) received PBS (5 μl). Intact control group (n=9) received no treatments. Two groups of L-AA-treated (n=5) and sham-operated (n=5) rats were intraperitoneally injected with alpha-methyl-p-tyrosine (a-MT, 100 mg/kg) one hour before locomotor activity testing. After intrastriatal injections effect of L-AA administration on locomotor activity was evaluated on the 3-rd day in open field and beam walking tests. Immunohistochemical localization of neuronal and astrocyte markers such as GFAP, glutamine synthetase, tyrosine hydroxylase and NeuN in striatum of randomly selected L-AA-treated (n=5) and sham-operated (n=5) animals was examined. Results: Intrastriatal L-AA administration led to astrocytic degeneration in the injection site. No neuronal degeneration and disruption of nigrostriatal dopaminergic terminals in striatum were detected in 72 hours after L-AA injection. Astrocyte ablation in striatum resulted in reduced motor activity and asymmetrical gait disturbances. Dopamine depletion facilitated bradykinesia caused by astrocyte ablation. Conclusion. These findings demonstrate a role of astroglia in motor function regulation in the nigrostriatal system and suggest the possible association of glial dysfunction with motor dysfunction in PD.

scholarly journals Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sepideh Nikfarjam ◽  
Jafar Rezaie ◽  
Naime Majidi Zolbanin ◽  
Reza Jafari
Keyword(s):  
Translational Medicine ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Live Cells ◽  
Therapeutic Effects ◽  
Paracrine Factors ◽  
Modern Approach ◽  
Safety Risks ◽  
Donor Cells ◽  
Kidney Liver

AbstractMesenchymal stem cells (MSCs) have captured great attention in regenerative medicine for over a few decades by virtue of their differentiation capacity, potent immunomodulatory properties, and their ability to be favorably cultured and manipulated. Recent investigations implied that the pleiotropic effects of MSCs is not associated to their ability of differentiation, but rather is mediated by the secretion of soluble paracrine factors. Exosomes, nanoscale extracellular vesicles, are one of these paracrine mediators. Exosomes transfer functional cargos like miRNA and mRNA molecules, peptides, proteins, cytokines and lipids from MSCs to the recipient cells. Exosomes participate in intercellular communication events and contribute to the healing of injured or diseased tissues and organs. Studies reported that exosomes alone are responsible for the therapeutic effects of MSCs in numerous experimental models. Therefore, MSC-derived exosomes can be manipulated and applied to establish a novel cell-free therapeutic approach for treatment of a variety of diseases including heart, kidney, liver, immune and neurological diseases, and cutaneous wound healing. In comparison with their donor cells, MSC-derived exosomes offer more stable entities and diminished safety risks regarding the administration of live cells, e.g. microvasculature occlusion risk. This review discusses the exosome isolation methods invented and utilized in the clinical setting thus far and presents a summary of current information on MSC exosomes in translational medicine.

Effects of Neuroinflammation on Neural Stem Cells

2016 ◽  
Vol 23 (1) ◽  
pp. 27-39 ◽  
Author(s):  
Ruxandra Covacu ◽  
Lou Brundin
Keyword(s):  
Immune Responses ◽  
Subventricular Zone ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Adaptive Immune ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
And Migration ◽  
The Brain ◽  
Proliferation And Migration

Neural stem/progenitor cells (NSCs/NPCs) are present in different locations in the central nervous system. In the subgranular zone (SGZ) there is a constant generation of new neurons under normal conditions. New neurons are also formed from the subventricular zone (SVZ) NSCs, and they migrate anteriorly as neuroblast to the olfactory bulb in rodents, whereas in humans migration is directed toward striatum. Most CNS injuries elicit proliferation and migration of the NSCs toward the injury site, indicating the activation of a regenerative response. However, regeneration from NSC is incomplete, and this could be due to detrimental cues encountered during inflammation. Different CNS diseases and trauma cause activation of the innate and adaptive immune responses that influence the NSCs. Furthermore, NSCs in the brain react differently to inflammatory cues than their counterparts in the spinal cord. In this review, we have summarized the effects of inflammation on NSCs in relation to their origin and briefly described the NSC activity during different neurological diseases or experimental models.

Mitochondria and neuronal activity

2007 ◽  
Vol 292 (2) ◽  
pp. C641-C657 ◽  
Author(s):  
Oliver Kann ◽  
Richard Kovács
Keyword(s):  
Energy Metabolism ◽  
Neuronal Activity ◽  
Mitochondrial Function ◽  
Imaging Techniques ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Metabolic Dysfunction ◽  
Membrane Excitability ◽  
Spatiotemporal Resolution ◽  
Atp Production

Mitochondria are central for various cellular processes that include ATP production, intracellular Ca2+ signaling, and generation of reactive oxygen species. Neurons critically depend on mitochondrial function to establish membrane excitability and to execute the complex processes of neurotransmission and plasticity. While much information about mitochondrial properties is available from studies on isolated mitochondria and dissociated cell cultures, less is known about mitochondrial function in intact neurons in brain tissue. However, a detailed description of the interactions between mitochondrial function, energy metabolism, and neuronal activity is crucial for the understanding of the complex physiological behavior of neurons, as well as the pathophysiology of various neurological diseases. The combination of new fluorescence imaging techniques, electrophysiology, and brain slice preparations provides a powerful tool to study mitochondrial function during neuronal activity, with high spatiotemporal resolution. This review summarizes recent findings on mitochondrial Ca2+ transport, mitochondrial membrane potential (ΔΨm), and energy metabolism during neuronal activity. We will first discuss interactions of these parameters for experimental stimulation conditions that can be related to the physiological range. We will then describe how mitochondrial and metabolic dysfunction develops during pathological neuronal activity, focusing on temporal lobe epilepsy and its experimental models. The aim is to illustrate that 1) the structure of the mitochondrial compartment is highly dynamic in neurons, 2) there is a fine-tuned coupling between neuronal activity and mitochondrial function, and 3) mitochondria are of central importance for the complex behavior of neurons.

scholarly journals Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eystein Oveland ◽  
Intakhar Ahmad ◽  
Ragnhild Reehorst Lereim ◽  
Ann Cathrine Kroksveen ◽  
Harald Barsnes ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Frontal Cortex ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Label Free ◽  
Immune Mediated ◽  
Multiple Sclerosis Patients ◽  
Protein Alterations ◽  
Disease Stages ◽  
Fluid Levels

AbstractTwo pathophysiological different experimental models for multiple sclerosis were analyzed in parallel using quantitative proteomics in attempts to discover protein alterations applicable as diagnostic-, prognostic-, or treatment targets in human disease. The cuprizone model reflects de- and remyelination in multiple sclerosis, and the experimental autoimmune encephalomyelitis (EAE, MOG1-125) immune-mediated events. The frontal cortex, peripheral to severely inflicted areas in the CNS, was dissected and analyzed. The frontal cortex had previously not been characterized by proteomics at different disease stages, and novel protein alterations involved in protecting healthy tissue and assisting repair of inflicted areas might be discovered. Using TMT-labelling and mass spectrometry, 1871 of the proteins quantified overlapped between the two experimental models, and the fold change compared to controls was verified using label-free proteomics. Few similarities in frontal cortex between the two disease models were observed when regulated proteins and signaling pathways were compared. Legumain and C1Q complement proteins were among the most upregulated proteins in cuprizone and hemopexin in the EAE model. Immunohistochemistry showed that legumain expression in post-mortem multiple sclerosis brain tissue (n = 19) was significantly higher in the center and at the edge of white matter active and chronic active lesions. Legumain was associated with increased lesion activity and might be valuable as a drug target using specific inhibitors as already suggested for Parkinson’s and Alzheimer’s disease. Cerebrospinal fluid levels of legumain, C1q and hemopexin were not significantly different between multiple sclerosis patients, other neurological diseases, or healthy controls.

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