Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes

NeuroToxicology, Journal Year: 2017, Volume and Issue: 64, P. 204 - 218

Published: May 21, 2017

Chronic manganese (Mn) exposure induces neurotoxicity, which is characterized by Parkinsonian symptoms resulting from impairment in the extrapyramidal motor system of basal ganglia. Mitochondrial dysfunction and oxidative stress are considered key pathophysiological features Mn neurotoxicity. Recent evidence suggests astrocytes as a major target neurotoxicity since accumulates predominantly astrocytes. However, primary mechanisms underlying Mn-induced astroglial its role metal not completely understood. In this study, we examined interrelationship between mitochondrial astrocytic inflammation We first evaluated whether alters bioenergetics cultured Metabolic activity assessed MTS assay revealed an IC50 92.68μM at 24h mouse (PMAs) 50.46μM human U373 cell line. treatment reduced mass, indicative impaired function biogenesis, was substantiated significant reduction mRNA mitofusin-2, protein that serves ubiquitination for mitophagy. Furthermore, increased circularity indicating augmented fission. Seahorse analysis status Mn-treated significantly oxygen consumption rate well ATP-linked respiration rate. The effect on energy deficits further supported ATP production. Mn-exposed also exhibited severely quiescent phenotype, inability oligomycin to increase extracellular acidification Since regulate immune functions CNS, modulates inflammation. only stimulated release proinflammatory cytokines, but exacerbated inflammatory response induced aggregated α-synuclein. novel mitochondria-targeted antioxidant, mito-apocynin, attenuated gene expression, supporting mitochondria mediating astrogliosis. Lastly, intranasal delivery vivo elevated GFAP depressed TH levels olfactory bulbs, clearly involvement dopaminergic Collectively, our study demonstrates drives events impairing bioenergetics.

Language: Английский

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MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

The FASEB Journal, Journal Year: 2019, Volume and Issue: 33(7), P. 8648 - 8665

Published: April 17, 2019

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for chronic inflammatory reaction mediated microglial cells in brain particularly strong PD. In our previous study, we have shown that brain-specific microRNA-124 (miR-124) significantly down-regulated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model PD it can also inhibit neuroinflammation during development However, further investigation required understand whether abnormal expression miR-124 regulates activation. this found sequestosome 1 (p62) phospho-p38 mitogen-activated protein kinases (p-p38) showed significant increase LPS-treated immortalized murine cell line BV2 an MPTP-induced Knockdown p62 could suppress secretion proinflammatory cytokines p-p38 microglia. Besides, inhibition p38 suppressed promoted autophagy cells. Moreover, study first identify unique role mediating response targeting culture supernatant transfer model, knockdown prevented apoptosis death human neuroblastoma lines SH-SY5Y (SH-SY5Y) following microglia addition, exogenous delivery attenuate activation substantia nigra par compacta MPTP-treated mice. Taken together, data suggest p62, p38, autophagy, indicating be potential therapeutic target regulating PD.-Yao, L., Zhu, Z., Wu, J., Zhang, Y., H., Sun, X., Qian, C., Wang, B., Xie, S., Lu, G. MicroRNA-124 p62/p38 promotes pathogenesis disease.

Language: Английский

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Dual Role of Autophagy in Diseases of the Central Nervous System

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: May 28, 2019

Autophagy is a vital lysosomal degradation and recycling pathway in the eukaryotic cell, responsible for maintaining an intricate balance between cell survival death, necessary neuronal function. This dual role played by autophagy raises question whether this process protective or destructive pathway, contributor of death failed attempt to repair aberrant processes? De-regulated at different steps excessive downregulated, has been proposed be associated with neurodegenerative disorders such as Alzheimer's-, Huntington's- Parkinson's-disease, known their intracellular accumulation protein aggregates. Recent observations impaired also appeared psychiatric schizophrenia bipolar disorder suggesting additional contribution pathophysiology mental illness. Here we review current understanding autophagy's various neuropsychiatric and, hitherto, prevailing new potential autophagy-related therapeutic strategies treatment.

Language: Английский

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The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

Biomolecules, Journal Year: 2020, Volume and Issue: 10(7), P. 1068 - 1068

Published: July 17, 2020

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced cytosol, it is oxidized mitochondria where fuels citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into through recently identified mitochondrial pyruvate carrier (MPC). In this review, we report latest findings on physiology MPC discuss how dysfunctional can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, cancer.

Language: Английский

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Circular RNA circDLGAP4 exerts neuroprotective effects via modulating miR-134-5p/CREB pathway in Parkinson’s disease

Biochemical and Biophysical Research Communications, Journal Year: 2019, Volume and Issue: 522(2), P. 388 - 394

Published: Nov. 21, 2019

Language: Английский

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An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease

Science Translational Medicine, Journal Year: 2020, Volume and Issue: 12(573)

Published: Dec. 9, 2020

Blocking epoxide hydrolase with a bioavailable small-molecule inhibitor reduces neuropathology in an Alzheimer’s disease mouse model.

Language: Английский

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New Perspectives on Roles of Alpha-Synuclein in Parkinson’s Disease

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: Nov. 21, 2018

Parkinson's disease (PD) is one of the spectrum disorders collectively termed synucleinopathies that typified by presence intraneuronal protein inclusions composed primarily misfolded and aggregated forms alpha-synuclein (α-syn), toxicity which has been attributed to transition from an α-helical conformation a β-sheet–rich structure polymerizes form toxic oligomers, could spread initiate formation "LB–like aggregates," transcellular mechanisms with seeding subsequent permissive templating. This "prion-like hypothesis" postulates α-syn prion-like pathological agent responsible for progression Parkinson pathology. Moreover, involvement inflammatory response in PD pathogenesis reported excessive microglial activation production proinflammatory cytokines. At last, treatments designed block release uptake pathogenic protein, especially increase its extracellular clearance, inhibit assembly transmission, seem be available therapies slow or halt progression.

Language: Английский

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The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

Movement Disorders, Journal Year: 2019, Volume and Issue: 35(1), P. 34 - 44

Published: Nov. 15, 2019

ABSTRACT The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark PD. Overexpression α‐syn failure cellular protein degradation systems play a major role in aggregation. discovery PD‐associated genes related to autophagic‐lysosomal pathway, such as VPS35 , LRRK2 GBA1 SMPD1 GALC ASAH1 SCARB2 CTSD CTSB GLA confirms involvement clearance dysfunction PD pathogenesis. Of importance, lysosomal enzyme activity is altered both genetic sporadic Decreased enzymes activities were measured same brain regions where accumulates, suggesting that crosstalk between aggregation impairment may exist. understanding pathway dysfunctions’ pathogenesis progression synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, evidences mechanisms reciprocal relation misfolded propagation are reviewed, together with most promising compounds targeting restoration disease‐modifying strategy treatment. © 2019 International Parkinson Movement Disorder Society

Language: Английский

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Pharmacological advances in mitochondrial therapy

EBioMedicine, Journal Year: 2021, Volume and Issue: 65, P. 103244 - 103244

Published: Feb. 26, 2021

Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis demise. An increasingly higher number pathologies is linked with mitochondrial dysfunction, which can arise from either genetic defects affecting core components or malfunctioning pathways impairing homeostasis. As such, mitochondria considered an important target several spanning neoplastic to neurodegenerative diseases as well metabolic syndromes. In this review we provide overview the state-of-the-art pharmacology, focusing on novel compounds that have been generated bid correct aberrations. Our work aims serve scientific community working translational medical science by highlighting most promising pharmacological approaches dysfunction disease.

Language: Английский

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Targeting α-Synuclein in Parkinson’s Disease: Progress Towards the Development of Disease-Modifying Therapeutics

Drugs, Journal Year: 2019, Volume and Issue: 79(8), P. 797 - 810

Published: April 13, 2019

Language: Английский

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