Function and therapeutic value of astrocytes in neurological diseases

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(5), P. 339 - 358

Published: Feb. 16, 2022

Language: Английский

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A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Feb. 11, 2020

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated neurodegenerative diseases. While genetic environmental factors influence amyloid formation, molecular triggers and/or facilitators not well defined. Growing evidence suggests that non-identical proteins may accelerate reciprocal aggregation in prion-like fashion. humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli cell surface abundantly expressed by certain bacteria. In mice overexpressing human α-synuclein (αSyn), we reveal colonization curli-producing Escherichia coli promotes αSyn pathology brain. Curli expression is required for E. exacerbate αSyn-induced behavioral deficits, including intestinal motor impairments. Purified subunits biochemical assays, while oral treatment gut-restricted inhibitor prevents curli-mediated acceleration abnormalities. We propose exposure microbial amyloids gastrointestinal tract disease

Language: Английский

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Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy

Redox Biology, Journal Year: 2021, Volume and Issue: 44, P. 102010 - 102010

Published: May 25, 2021

Activated microglia are an important type of innate immune cell in the brain, and they secrete inflammatory cytokines into extracellular milieu, exert neurotoxicity to surrounding neurons involved pathogenesis many brain disorders. Quercetin (Qu), a natural flavonoid, is known have anti-inflammatory antioxidant properties. Previous studies shown that both increased reactive oxygen species (ROS) stress decreased autophagy participate activation microglial. In current study, we showed Qu significantly attenuated LPS-induced factor production, proliferation NF-κB microglia. Importantly, levels NLR family, pyrin domain containing three (NLRP3) inflammasome pyroptosis-related proteins, including NLRP3, active caspase-1, GSDMD N-terminus cleaved IL-1β. Further study indicated this effect was associated with mitophagy regulation. promoted enhance damaged mitochondrial elimination, which then reduced mtROS accumulation alleviated NLRP3 activation. Then, confirmed treatment protected primary against microglial toxicity neurodegeneration depression PD mouse models. IL-1β administration blunted these neuroprotective effects vitro vivo. This work illustrated prevents neuronal injury via inhibition mtROS-mediated through promoting mitophagy, provides potential novel therapeutic strategy for neuroinflammation-related diseases.

Language: Английский

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Determinants of dopaminergic neuron loss in Parkinson's disease

FEBS Journal, Journal Year: 2018, Volume and Issue: 285(19), P. 3657 - 3668

Published: July 20, 2018

The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death dopaminergic neurons in substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated PD pathogenesis, but until recently it was unclear why SNc should be particularly vulnerable to these two types insult. In this brief review, evidence that an anatomical, physiological, biochemical phenotype predisposes them synuclein is summarized. recognition certain traits may predispose PD-linked creates translational opportunities for slowing or stopping progression.

Language: Английский

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MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration

Cell Death and Differentiation, Journal Year: 2018, Volume and Issue: 26(2), P. 213 - 228

Published: May 21, 2018

Abstract Parkinson's disease (PD) is a progressive neurodegenerative characterized by the loss of dopaminergic neurons in substantia nigra (SN) and reduction dopamine levels striatum. Although details molecular mechanisms underlying neuronal death PD remain unclear, neuroinflammation also considered potent mediator pathogenesis progression PD. In present study, we evidences that microglial NLRP3 inflammasome activation critical for subsequent motor deficits 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model Specifically, deficiency significantly reduces dysfunctions neurodegeneration MPTP-treated mice. Furthermore, abolishes MPTP-induced recruitment, interleukin-1β production caspase-1 SN brain. primary microglia mixed glial cell cultures, MPTP/ATP treatment promotes robust assembly via producing mitochondrial reactive oxygen species. Consistently, 1-methyl-4-phenyl-pyridinium (MPP + ) induces presence ATP or nigericin bone-marrow-derived macrophages. These findings reveal novel priming role neurotoxin MPTP MPP activation. Subsequently, inflammasome-active profound microglia-neuron co-culture model. Cx3Cr1 CreER -based microglia-specific expression an active mutant greatly exacerbates Taken together, our results indicate plays pivotal

Language: Английский

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