Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2017, Volume and Issue: 3(1)

Published: Oct. 11, 2017

The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson's disease (PD). However, inter-relationship between defects neuroinflammation not well understood. In present study, we show that impaired function can augment inflammasome-driven proinflammatory cascade microglia. Primary mouse microglia treated with common inflammogen LPS increased pro-IL-1β expression. Interestingly, exposure LPS-primed microglial cells complex-I inhibitory pesticides rotenone tebufenpyrad specifically potentiated induction, ASC speck formation processing IL-1β dose-dependent manner, indicating impairment heightened inflammasome-mediated response neurotoxic pesticide-induced activation was accompanied by bioenergetic lysosomal Furthermore, enhanced ROS generation primary microglia, while amelioration mitochondria-derived mitochondria-targeted antioxidant mito-apocynin completely abolished release, drives potentiation Exposure conditioned media obtained from inhibitor-treated, cells, but unprimed induced dopaminergic neurodegeneration cultured mesencephalic human neuronal (LUHMES). Notably, our vivo results rodent models PD further support due dysfunction. Collectively, demonstrate amplify signaling, which augments process.

Language: Английский

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Metals associated neurodegeneration in Parkinson’s disease: Insight to physiological, pathological mechanisms and management

Neuroscience Letters, Journal Year: 2021, Volume and Issue: 753, P. 135873 - 135873

Published: April 2, 2021

Language: Английский

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Mitochondrial dysfunction: A fatal blow in depression

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 167, P. 115652 - 115652

Published: Oct. 4, 2023

Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining metabolic balance through intracellular Ca2+ homeostasis, oxidative stress, axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to hippocampal neurons key component plasticity regulation synapses plays critical role mechanism depression. There evidence suggesting that mitochondrial dysfunction associated synaptic impairment. The maintenance homeostasis includes quantitative quality control mitochondria. Mitochondrial biogenesis produces new healthy mitochondria, dynamics cooperates mitophagy remove damaged These processes population stability exert neuroprotective effects against early In contrast, observed various brain regions patients major depressive disorders. accumulation defective mitochondria accelerates dysfunction. addition, impaired aggravate alterations microenvironment, promoting neuroinflammation depletion, thereby exacerbating development This review summarizes influence underlying molecular pathways on pathogenesis Additionally, we discuss as potential therapeutic strategy for

Language: Английский

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Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 2, 2025

Language: Английский

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Environmental neurotoxic pollutants: review

Environmental Science and Pollution Research, Journal Year: 2020, Volume and Issue: 27(33), P. 41175 - 41198

Published: Aug. 20, 2020

Language: Английский

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Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells

Science Signaling, Journal Year: 2019, Volume and Issue: 12(563)

Published: Jan. 8, 2019

Exosomes containing the adaptor ASC spread NLRP3 inflammasome activation between cells after manganese exposure.

Language: Английский

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The effects of manganese overexposure on brain health

Neurochemistry International, Journal Year: 2020, Volume and Issue: 135, P. 104688 - 104688

Published: Jan. 20, 2020

Language: Английский

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Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes

Autophagy, Journal Year: 2019, Volume and Issue: 16(8), P. 1506 - 1523

Published: Nov. 6, 2019

Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks neurodegenerative diseases. It is widely accepted autophagic dysfunction involved in pathogenesis various disorders; however, the role regulation macroautophagy/autophagy unclear. Here, we show manganese (Mn) induces a decline nuclear localization TFEB (transcription factor EB), master regulator autophagy-lysosome pathway, leading astrocytes mouse striatum. We further Mn suppresses autophagic-lysosomal degradation mitochondria accumulation unhealthy mitochondria. Activation autophagy by rapamycin or overexpression ameliorates Mn-induced mitochondrial respiratory reactive oxygen species (ROS) generation astrocytes, suggesting causal relation between failure toxicity. Taken together, our data demonstrate inhibits activity, impaired causally related astrocytes. These findings reveal previously unappreciated for dysregulation identify as potential therapeutic target mitigate toxicity.Abbreviations BECN1: beclin 1; CTSD: cathepsin D; DMEM: Dulbecco's Modified Eagle Medium; GFAP: glial fibrillary acid protein; GFP: green fluorescent HBSS: hanks balanced salt solution; LAMP: lysosomal-associated membrane LDH: lactate dehydrogenase; Lys Inh: lysosomal inhibitors; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated kinase; Mn: manganese; MTOR: mechanistic OCR: consumption rate; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PI: propidium iodide; ROS: species; s.c.: subcutaneous; SQSTM1/p62: sequestosome TEM: transmission electron microscopy; TFEB: transcription EB

Language: Английский

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Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: unknown

Published: June 28, 2020

Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation these can provide potential treatments halt progression. Here, we demonstrated that Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated response aggregated α-synuclein (αSynAgg) stimulation primary cultures animal models PD, as well postmortem human PD brains. Patch-clamp electrophysiological studies confirmed observed Kv1.3 upregulation translated increased channel activity. The kinase Fyn, risk factor for modulated transcriptional posttranslational modification Kv1.3. Multiple state-of-the-art analyses, Duolink proximity ligation assay imaging, revealed Fyn directly bound posttranslationally modified its Furthermore, functional relevance augmenting neuroinflammatory by using Kv1.3-KO microglia Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting importance neuroinflammation. Administration PAP-1 significantly inhibited neurodegeneration neuroinflammation multiple PD. Collectively, our results imply Fyn-dependent regulation channels plays an obligatory role accentuating identify therapeutic target

Language: Английский

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Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4646 - 4646

Published: April 28, 2021

Understanding of the immediate mechanisms Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary recent findings in field, with an emphasis clarify existing gaps and future research directions. provide, here, brief review pertinent discoveries related from last five years. Significant progress was achieved understanding role Mn transporters, such as SLC39A14, SLC39A8, SLC30A10, regulation systemic brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered targets, including oxidative stress, endoplasmic reticulum apoptosis, neuroinflammation, cell signaling pathways, interference neurotransmitter metabolism, name few. Recent have also demonstrated impact exposure on transcriptional these pathways. There significant autophagy protective mechanism against cytotoxic neurotoxicity, yet for induce autophagic flux itself dysfunction under conditions decreased bioavailability. This ambivalent may at crossroad mitochondrial dysfunction, apoptosis. Yet very evidence suggests can toxic impacts below no observed adverse effect dysfunction. The supramolecular complexes SNARE NLRP3 inflammasome greatly contributes synaptic respectively. aforementioned effects might least partially mediated by α-synuclein accumulation. In addition impaired neurotransmission shown systems their complex interplay. Although novel been highlighted, additional studies are required identify critical targets neurotoxicity.

Language: Английский

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