Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration

Nature Neuroscience, Journal Year: 2019, Volume and Issue: 22(10), P. 1635 - 1648

Published: Sept. 23, 2019

Language: Английский

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Neurotoxicity of pesticides

Acta Neuropathologica, Journal Year: 2019, Volume and Issue: 138(3), P. 343 - 362

Published: June 13, 2019

Language: Английский

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Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Movement Disorders, Journal Year: 2019, Volume and Issue: 35(1), P. 20 - 33

Published: Nov. 4, 2019

Abstract Excessive activation of microglia and subsequent release proinflammatory cytokines play a crucial role in neuroinflammation neurodegeneration Parkinson's disease (PD). Components the nucleotide‐binding oligomerization domain leucine‐rich‐repeat‐ pyrin‐domain‐containing 3 inflammasome complex, 3, caspase‐1, apoptosis‐associated speck‐like protein containing CARD, are highly expressed activated PD patient brains. Findings suggest that neurotoxins, aggregation α‐synuclein, mitochondrial reactive oxygen species, disrupted mitophagy key regulators microglial interleukin‐1β interleukin‐18 caspase‐1‐mediated pyroptotic cell death substantia nigra brain. Although this evidence suggests may be potential drug target for treatment PD, exact mechanism how sense these stimuli initiate signaling is unknown. Here, molecular regulation its pathogenesis discussed. Moreover, both endogenous synthetic modulators, long noncoding RNA, microRNA to develop novel therapeutics treat presented. Overall, we recommend can treatment. © 2019 International Parkinson Movement Disorder Society

Language: Английский

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Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia

The Journal of Experimental Medicine, Journal Year: 2019, Volume and Issue: 216(6), P. 1411 - 1430

Published: April 29, 2019

Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson’s disease (PD), but cell-signaling mechanisms governing chronic are not well understood. Here, we show that Fyn kinase, in conjunction with class B scavenger receptor CD36, regulates microglial uptake aggregated human α-synuclein (αSyn), which component PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation NLRP3 inflammasome. kinase both these processes; it mediates PKCδ-dependent NF-κB–p65 nuclear translocation, leading inflammasome priming, facilitates import into microglia, contributing generation mitochondrial reactive oxygen species consequently activation. In vivo experiments using A53T viral-αSyn overexpression mouse models as PD neuropathological results further confirm role Collectively, our study identifies novel Fyn-mediated signaling mechanism amplifies PD.

Language: Английский

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Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Journal of Parkinson s Disease, Journal Year: 2020, Volume and Issue: 11(1), P. 45 - 60

Published: Oct. 13, 2020

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from observation that mitochondrial toxins cause PD, findings genetic PD supported contribution to disease. Here, proteins encoded by autosomal recessively inherited genes Parkin, PTEN-induced kinase 1 (PINK1), DJ-1 are involved pathways. Additional evidence for stems models autosomal-dominant due mutations alpha-synuclein (SNCA) leucine-rich repeat 2 (LRRK2). Moreover, patients harboring alterations polymerase gamma (POLG) often exhibit signs parkinsonism. While some molecular studies suggest is primary event others speculate it result impaired clearance. Most recent research even implicated damage-associated patterns released non-degraded mitochondria neuroinflammatory processes PD. we summarize manifold literature dealing with context light advances field personalized medicine, patient stratification according degree impairment followed enhancement therapy may hold potential at least subset cases. Thus, second part this review, discuss therapeutic approaches targeting aim prevent or delay neurodegeneration

Language: Английский

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Immunometabolism in the Brain: How Metabolism Shapes Microglial Function

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(11), P. 854 - 869

Published: Sept. 18, 2020

Language: Английский

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Andrographolide suppresses NLRP3 inflammasome activation in microglia through induction of parkin-mediated mitophagy in in-vitro and in-vivo models of Parkinson disease

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 142 - 158

Published: Sept. 22, 2020

Language: Английский

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Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Nov. 5, 2020

Alzheimer's disease (AD) is an incurable neurodegenerative disease. Numerous studies have demonstrated a critical role for dysregulated glucose metabolism in its pathogenesis. In this review, we summarize metabolic alterations aging brain and AD-related deficits associated with dysregulation, glycolysis dysfunction, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) deficits, pentose phosphate pathway impairment. Additionally, discuss recent treatment strategies targeting defects AD, including their limitations, effort to encourage the development of novel therapeutic strategies.

Language: Английский

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Neurodegenerative Disease and the NLRP3 Inflammasome

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: March 10, 2021

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by progressive neuronal loss the brain or peripheral nervous system, generally involve protein aggregation, as well metabolic abnormalities immune dysregulation. Although vast majority neurodegeneration idiopathic, there many known genetic environmental triggers. In past decade, research exploring low-grade systemic inflammation its impact on development progression increased. A particular focus been whether arises only secondary effect also cause pathology. inflammasomes, more specifically NLRP3 inflammasome, crucial component innate usually activated response infection tissue damage. Dysregulation inflammasome implicated several disorders, such Alzheimer’s disease, Parkinson’s Huntington’s amyotrophic lateral sclerosis, prion diseases. This review aims summarise current literature role pathogenesis diseases, work investigating inhibition potential future therapy.

Language: Английский

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The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 12

Published: May 26, 2021

Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by motor symptoms of bradykinesia, rigidity and resting tremor non-motor sleep disturbances, constipation, depression. Pathological hallmarks include neuroinflammation, degeneration dopaminergic neurons in substantia nigra pars compacta, accumulation misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies neurites. Microglia astrocytes are essential to maintaining homeostasis within central nervous system (CNS), including providing protection through process gliosis. However, dysregulation glial cells results disruption leading a chronic pro-inflammatory, deleterious environment, implicated numerous CNS diseases. Recent evidence has demonstrated role for peripheral immune cells, particular T lymphocytes pathogenesis PD. These infiltrate CNS, accumulate nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding induce neuronal cell death. Indeed, greater understanding integrated network communication that exists between may increase our hence provide novel therapeutic approaches.

Language: Английский

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