Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice

Science Signaling, Journal Year: 2024, Volume and Issue: 17(829)

Published: March 26, 2024

Mutations in the gene encoding lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and considered strongest genetic risk factor Parkinson’s (PD) Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) cells contributes neuropathology GD, PD, LBD by triggering chronic neuroinflammation. Here, we investigated mechanisms which GC induces We found that within microglia induced pharmacological inhibition triggered STING-dependent inflammation, contributed neuronal loss both vitro vivo. mitochondrial DNA (mtDNA) leakage cytosol trigger inflammation. Rapamycin, a compound promotes activity, improved function, thereby decreasing STING signaling. Furthermore, damage caused led defects degradation activated STING, further exacerbating inflammation mediated microglia. Thus, limiting activity may be strategy suppress neuroinflammation deficiency.

Language: Английский

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Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives

Physiological Reviews, Journal Year: 2024, Volume and Issue: 105(1), P. 137 - 207

Published: July 11, 2024

Lipids represent the most abundant molecular type in brain, with a fat content of ∼60% dry brain weight humans. Despite this fact, little attention has been paid to circumscribe dynamic role lipids function and disease. Membrane such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid, endocannabinoids finely regulate both synaptic receptors ion channels that ensure critical neural functions. After brief introduction on their respective properties, we review here regulating channel activity, action potential propagation, neuronal development, functional plasticity contribution development neurological neuropsychiatric diseases. We also provide possible directions for future research lipid

Language: Английский

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Multi-omics profiling reveals rhythmic liver function shaped by meal timing

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 29, 2023

Post-translational modifications (PTMs) couple feed-fast cycles to diurnal rhythms. However, it remains largely uncharacterized whether and how meal timing organizes rhythms beyond the transcriptome. Here, we systematically profile daily of proteome, four PTMs (phosphorylation, ubiquitylation, succinylation N-glycosylation) lipidome in liver from young female mice subjected either day/sleep time-restricted feeding (DRF) or night/wake (NRF). We detect robust among different layers omics with phosphorylation most nutrient-responsive least. Integrative analyses reveal that clock regulation fatty acid metabolism represents a key feature is reset by timing, as indicated rhythmic circadian repressor PERIOD2 at Ser971 (PER2-pSer971). confirm PER2-pSer971 activated nutrient availability vivo. Together, this dataset comprehensive resource detailing proteomic lipidomic responses alterations timing.

Language: Английский

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Glia: The Cellular Glue that binds Circadian Rhythms and Sleep

SLEEP, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Glia are increasingly appreciated as serving an important function in the control of sleep and circadian rhythms. Glial cells Drosophila mammals regulate daily rhythms locomotor activity well homeostatic rebound following deprivation. In addition, they contribute to proposed functions sleep, with different mapping varied glial subtypes. Here, we discuss recent findings rodent models establishing a role glia or regulation synaptic plasticity, brain metabolism, removal cellular debris immune challenges. These underscore relevance for benefits attributed have implications understanding neurobiological mechanisms underlying associated disorders.

Language: Английский

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Brain lipidomic profiles of sleep enhancement through co‐administration of alprazolam and CGS21680

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Alprazolam and CGS21680 are both drugs known for their sleep sedation effects. The study aimed to utilize mass spectrometry imaging assess the regulatory changes in brain lipids of mice by sleep‐enhancing effects co‐administration alprazolam CGS21680. A seven‐day continuous administration mouse model was established using Glycerophosphoinositols were elevated nine regions, glycerophosphoglycerols rising six glycerophosphoserines increasing regions. Other lipid classes exhibited reductions, with fatty acids decreasing 10 carnitines seven ceramides diacylglycerols research provides valuable insights into sleep‐related regulation pathways delineating various biomarkers multiple

Language: Английский

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Circadian Biology and the Neurovascular Unit

Circulation Research, Journal Year: 2024, Volume and Issue: 134(6), P. 748 - 769

Published: March 14, 2024

Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect as well mechanisms disease in central nervous system. In this review, we attempt survey synthesize emerging studies investigate how circadian biology may influence neurovascular unit. We examine clocks operate neural, glial, vascular compartments, review regulate cell-cell signaling, assess interactions with aging comorbidities, finally ask whether effects disruptions risk progression pathophysiology cerebrovascular disease. Overcoming identified challenges leveraging opportunities for future research might support development novel circadian-based treatments stroke.

Language: Английский

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Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 11, 2024

Abstract Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of central nervous system (CNS). Through transcriptomics imaging analyses, we have identified Obp44a as one most abundantly produced proteins from Drosophila CNS glia. Protein structure homology modeling Nuclear Magnetic Resonance (NMR) experiments reveal a fatty acid binding protein (FABP) with high affinity towards long-chain acids both native oxidized forms. Further analyses demonstrate that effectively infiltrates neuropil, traffics between neuron glia, is secreted into hemolymph, acting lipid chaperone scavenger to regulate redox homeostasis developing brain. In agreement this essential role, deficiency leads anatomical behavioral deficits adult animals elevated levels. Collectively, our findings unveil crucial involvement noncanonical shuttle within outside brain, needed maintain healthy brain environment. These could inspire design novel approaches restore dysregulated diseases.

Language: Английский

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From seconds to days: Neural plasticity viewed through a lipid lens

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 80, P. 102702 - 102702

Published: March 23, 2023

Language: Английский

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Cholesterol is required for activity-dependent synaptic growth

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(22)

Published: Oct. 30, 2023

Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates levels these changes affect function. We generated transgenic flies that express the cholesterol-binding D4H domain perfringolysin O toxin found increased presynaptic terminals Drosophila larval neuromuscular junctions following activity. Reduced impaired growth largely prevented activity-dependent growth. Presynaptic knockdown adenylyl cyclase phenocopied caused by reducing cholesterol. Furthermore, effects knocking down were not additive, suggesting they function same pathway. Increasing cAMP using a dunce mutant with reduced phosphodiesterase failed to rescue this growth, functions downstream cAMP. used protein kinase A (PKA) sensor show PKA Collectively, our results demonstrate enhanced likely activate cAMP-PKA pathway

Language: Английский

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Sleep Promotion by 3-Hydroxy-4-Iminobutyric Acid in Walnut Diaphragma juglandis Fructus

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Insufficient sleep can produce a multitude of deleterious repercussions on various domains human well-being. Concomitantly, the walnut (Juglans mandshurica) confers numerous salutary biological activities pertaining to sleep. Nevertheless, sedative and hypnotic capacities walnut's functional constituents remain obscure. In this investigation, we analyzed components Diaphragma juglandis fructus innovatively discovered compound, defined as 3-hydroxy-4-iminobutyric acid (HIBA), which disrupts motor activity enhances duration by regulating neurotransmitters (GABA, DA, etc.) within brain serum mice. Subsequently, metabolomics approach serum, basal ganglia, hypothalamus, hippocampus well gut microbiota was undertaken unravel underlying molecular mechanisms promotion. Our data reveal that HIBA regulate metabolism ganglia (sphingolipids, acylcarnitines, etc.), possibly in relation HIBA's influence microbiome (Muribaculum, Bacteroides, Lactobacillus, etc.). Therefore, introduce novel natural product, HIBA, explicate modulation promotion mice based microbiota-gut-brain axis. This study contributes fresh insights toward product-based research.

Language: Английский

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