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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Metabolic Reprogramming of Neural Stem Cells by Chiral Nanofiber for Spinal Cord Injury

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Exogenous neural stem cells (NSCs) have great potential to reconstitute damage spinal circuitry. However, regulating the metabolic reprogramming of NSCs for reliable nerve regeneration has been challenging. This report discusses biomimetic dextral hydrogel (DH) with right-handed nanofibers that specifically reprograms lipid metabolism NSCs, promoting their differentiation and rapid damaged axons. The underlying mechanism is intrinsic stereoselectivity between DH fatty acid-binding protein 5 (FABP5), which facilitates transportation acids bound FABP5 into mitochondria endoplasmic reticulum, subsequently augmenting acid oxidation (FAO) levels enriching sphingosine biosynthesis. In rat SCI model, significantly improved Basso–Beattie–Bresnahan (BBB) locomotor scores (over 3-fold) hindlimbs' compound muscle action 4-fold) compared untreated group, conveying a significant return functional recovery. finding nanoscale chirality-dependent provides insights understanding cell physiology presents opportunities regenerative medicine.

Language: Английский

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Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis

Glia, Journal Year: 2023, Volume and Issue: 72(1), P. 167 - 183

Published: Sept. 5, 2023

Abstract The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia‐like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during transition from in NSC niche is not fully understood. Lipid metabolism lipid composition play important roles regulating fate determination. Biological membranes define individual cellular shape help maintain organization are highly heterogeneous structure there exist diverse microdomains (also known as rafts), which enriched with sugar molecules, such glycosphingolipids. An often overlooked but key aspect that functional activities of proteins genes dependent on their molecular environments. We previously reported ganglioside GD3 predominant species reduced pools observed global GD3‐synthase knockout (GD3S‐KO) mouse brains. specific determining stage cell‐lineage determination remain unclear, since GD3S‐KO mice cannot distinguish if regulates or developmental impacts. Here, we show inducible deletion promotes activation, resulting loss long‐term maintenance adult pools. subventricular zone (SVZ) dentate gyrus (DG) GD3S‐conditional‐knockout led impaired olfactory memory functions. Thus, our results provide convincing evidence maintains state niche.

Language: Английский

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Neural stem cells in aging

Translational Medicine of Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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Gangliosides in neural stem cell fate determination and nerve cell specification--preparation and administration

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

Published: June 11, 2024

Abstract Gangliosides are sialylated glycosphingolipids with essential but enigmatic functions in healthy and disease brains. GD3 is the predominant species neural stem cells (NSCs) GD3-synthase (sialyltransferase II; St8Sia1 ) knockout (GD3S-KO) revealed reduction of postnatal NSC pools severe behavioral deficits including cognitive impairment, depression-like phenotypes, olfactory dysfunction. Exogenous administration significantly restored enhanced stemness NSCs multipotency self-renewal, followed by neuronal functions. Our group discovered that involved maintenance fate determination interacting epidermal growth factor receptors (EGFRs), modulating expression cyclin-dependent kinase (CDK) inhibitors p27 p21, regulating mitochondrial dynamics via associating a fission protein, dynamin-related protein-1 (Drp1). Furthermore, we nuclear GM1 promotes differentiation an epigenetic regulatory mechanism. binds acetylated histones on promoter N-acetylgalactosaminyltransferase (GalNAcT; GM2 synthase (GM2S); B4galnt1) as well NeuroD1 differentiated neurons. In addition, activation GM2S gene was detected accompanied apparent induction responding to exogenous supplement GM1. Interestingly, induced tyrosine hydroxylase (TH) gene, recruitment Nurr1 PITX3, dopaminergic neuron-associated transcription factors, TH region. this way, epigenetically regulates neuron specific expression, it would modify Parkinson’s disease. Multifunctional gangliosides modulate lipid microdomains regulate important molecules multiple sites: plasma membrane, membrane. Versatile functional neurons sustain protein activities ganglioside microdomains. Maintaining proper benefits development millions senior citizens neurodegenerative diseases. Here, introduce how isolate administer them into mouse brain investigate their nerve cell specification.

Language: Английский

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Ganglioside GD2 Contributes to a Stem‐Like Phenotype in Intrahepatic Cholangiocarcinoma

Liver International, Journal Year: 2024, Volume and Issue: 45(1)

Published: Dec. 26, 2024

ABSTRACT Background & Aims GD2, a member of the ganglioside (GS) family (sialic acid‐containing glycosphingolipids), is potential biomarker cancer stem cells (CSC) in several tumours. However, possible role GD2 and its biosynthetic enzyme, GD3 synthase (GD3S), intrahepatic cholangiocarcinoma (iCCA) has not been explored. Methods The stem‐like subset two iCCA cell lines was enriched by sphere culture (SPH) compared to monolayer parental (MON). GS profiles were evaluated chromatography, after feeding with radioactive sphingosine. Membrane expression FACS, enzymes biosynthesis analysed RT‐qPCR. modulation features investigated vitro vivo using GD3S‐overexpressing corroborated global transcriptomic analysis. Results composition markedly different comparing SPH MON. Among complex GS, iCCA‐SPH showed increased levels, agreement high levels GM2/GD2 synthases. overexpressing GD3S had higher sphere‐forming ability, invasive properties drug resistance than cells. NOD/SCID mice implanted CCLP1 developed larger tumours control By analysis, ontology investigation identified 74 processes shared GD3S‐transfected cells, enrichment for development morphogenesis processes, MAPK signalling locomotion. In cohort patients iCCA, correlated lymph node invasion, indicating relevance clinical setting. Conclusions profile derivatives regulates

Language: Английский

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Multifunctional glycolipids as multi-targeting therapeutics for neural regeneration

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(4), P. 707 - 708

Published: Sept. 4, 2023

Many patients with neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases suffer from disease progression without any satisfying clinical intervention, likely due to our lack of knowledge on how normal aging impacts the pathogenic mechanisms these debilitating diseases. A growing body literature has emerged in recent years that clearly demonstrates involvement glycolipids protein-oligomerization disorders. We hypothesize changes composition are a common mechanism underlying shift healthy brain neuropathological processes To effectively treat AD PD, it is necessary eliminate cytotoxic oligomers amyloid-beta peptides (Aβs) alpha-synuclein (α-syn) sustain functional neurons. Based mouse study, we propose reduce neurotoxic amyloid β-proteins (Aβ) α-syn neurons brains by utilizing sugar-containing molecules called gangliosides strategy for Since important modulators proteins plasma membranes, cell nuclei, mitochondria, intracellular organelles, they expected modulate variety lipid microdomains restore their physiological function those living Limited endogenous neurogenesis, spontaneously occurs following various attacks, ischemic stroke, traumatic injury, Aβ, an attempt repair. However, adult mammalian low ability regenerate, making difficult fully recover lost functions. Our perspective adequate molecular environment glycolipid compositions able membrane protein activities, growth factor receptors and/or remodel chromatin structures enhance gene expressions regulating stemness differentiation stem/progenitor cells achieve repair damaged tissue. Proper components (e.g., GM1, GD3) conducive regeneration. The structural diversity localization surface glycolipid-enriched (also rafts or glycosynapses) place them ideal which can mediate intercellular interactions, adhesion, receptor function, signaling. Glycolipid dynamically changed during neural differentiation, e.g., ganglioside GD3 expressed stem-progenitor (early stage) other hand, GM1 (late stage differentiation), thereby distinct stages differentiation. published preliminary data demonstrated maintains stem (NSC) characteristics epigenetically promotes neuronal (Wang Yu, 2013; Tsai 2014; Wang et al., 2016; Tang 2021; Fuchigami 2023a, 2023b; Itokazu 2023; 2023). Cells well subcellular organelles surrounded biological membranes define individual cellular shape maintain organization. These semi-permeable essential creating chemical electrical gradients needed Recently, lipids have been revealed be not only separating extracellular environments but also providing platforms signalings. others specific control functions including plasma, mitochondrial, nuclear membranes. Signaling neurotrophic factors regulated gangliosides, epidermal 2013) glial cell-derived (GDNF) (Hadaczek 2015), preferentially reside at microdomain membrane. key aspect successful translational studies activities genes highly dependent upon environments. An example trial GDNF PD failed, all previously trials (Manfredsson 2020). expression microdomain) activation further Therefore, my opinion, alone (without GM1) could activate pathway. Decreased altered mitochondrial observed (Simmons Mitochondrial dysfunction would contribute etiopathology showed intranasally administered dramatically restored levels voltage-dependent anion channel 1, major component outer membrane, known regulate functions, wild-type substantia nigra cortex human A53T α-syn-overexpressing model (A53T) (Itokazu This result suggests intranasal infusion effective method Further, found regulates dynamics mediating turnover dynamin-related protein-1 (Tang 2021). binds Targeting another promising approach development future therapies With regard involved Ca2+ homeostasis was proposed modulator axonogenesis (Ledeen Wu, 2015). discovered epigenetic regulatory (Tsai 2016). Nuclear acetylated histones promoters GM2 synthase (GM2S; N-acetylgalactosaminyltransferase (GalNAcT)), critical enzyme synthesis, NeuroD1 differentiating Acetylation H3 H4 GM2S promoter leads recruitment trans-activation specificity 1 activating 2 In addition, detected accompanied apparent induction NSCs responding exogenous supplement GM1. indeed localized nucleus where interact transcriptionally active histones. increased receptor-related transcription maturation, maintenance midbrain dopaminergic 2021) GM2S-knockout (KO) mice. Further investigation induces tyrosine hydroxylase (TH) gene, augmentation TH region Neuro 2a cells. reduces patients' quality life relentless motor non-motor symptoms. reported molecule pathogenesis since high affinity stabilize alpha-helical state inhibit oligomerization. GM1-deficient mice exhibit PD-like movement disorders reduced (Wu 2011). aged GM1-depleted symptoms, impairment, striatal dopamine depletion, gastrointestinal dysfunction, cardiac pathology, cognitive suggesting deficiency neuropathologically correlates motor- symptoms humans. One neurogenic bladder causes urinary tract infection, resulting delirium, decline, falls, hospitalization. deficient dysregulation treatment diabetic rats. significance multifunctional rodent studies, versatile nature potential ameliorate several pathological features α-syn, signal inactivation, aberrant regulation, NSC toxic Aβ pathologic hallmarks PD. Several inhibits oligomerization increases accumulation, while role settled. brain-type significantly decreased AD, Huntington's (Magistretti 2019), correct target exciting data, nasal administration level, striatum 2021, Furthermore, neurogenesis subventricular zone/olfactory bulb dentate gyrus (Fuchigami 2023b). It desirable develop more strategies cure Although explored therapeutics viable therapeutic new delivered through non-injection routes will (Schneider, 2022). current problem efficient administering manner permits efficiently cross blood-brain barrier. limited delivery, intravenous intramuscular stroke spinal cord injury safe, no adverse effects, most importantly neurological improvement. Schneider's (summarized Schneider, 2022) subcutaneously injected beneficial effects improved PET-based transporter imaging less than 0.4% intravenously fluorinated derivative, F-GM1, enter non-human primate (monkey) brain. successfully developed convenient non-invasive delivery procedure gangliosides. Intranasal therapy slow improve As depend environments, microdomains, theory, may patients. roles studied glycosyltransferase null global KO cannot address if postnatal stage, loss before birth. inducible deletion radial glia-like acute activation, long-term pools 2023a). zone GD3S-conditional-KO led olfactory memory dysfunctions. Thus, results provide convincing evidence crucial niche. humans still under debate, detection certain regions supports author's others' hypothesis exhibits plasticity thought, this affects Emerging models level early/moderate onset disease, then becomes sluggish late/severe AD. Diminished aging, hypothesized accelerated pool one Impaired hippocampal signs deficits sustaining suggested prevention supplementation amplify numbers hippocampus help replenish circuits olfaction psychiatric early moderate sufficient On severe first support NSCs. Cell additional clues neuroprotections useful developing novel regeneration (Figure 1).Figure 1: Mechanism therapy.(A) Upper: Gangliosides prevent accumulation Aβ), neurotoxicity. Lower: facilitates binding AcH Nurr1, neuron-associated increase via opening chromatin. generates positive feedback loop produce (GM2S, synthesis). GM1-lipid domains serve docking site chromatins maintaining (B) Postnatal depletion impaired impairment EGFR (red) (blue)-rich surface. interaction responsible downstream signaling self-renewal associated fission protein-Drp1. Without GD3, Drp1 increased, fragmentation augmented. Deficiency developmental behavioral deficits, depression, hippocampus-dependent memory, dysfunction. (C) restores enhanced multipotency self-renewal, DCX+ combinational (GD3 had synergistic effect. supplements SVZ ganglioside-based (Bob Yu Method) promising. Created Microsoft PowerPoint. Aβ: Amyloid-beta peptide; AcH: histones; Ap-2: 2; α-syn: alpha-synuclein; DCX: doublecortin; DG: gyrus; Drp1: dynamin related protein-1; EGFR: receptor; GD3: disialoganglioside 3; GM1: monosialoganglioside 1; NPC: progenitor cell; NSC: Nurr1: NR4A2); OB: bulb; Sox2: SRY (sex determining Y)-box Sp1: SVZ: zone; TH: hydroxylase.This work dedicated Robert K. Yu). present supported National Institute Neurological Disorders Stroke grant (R01 NS100839), Sheffield Memorial Grant CSRA Disease Support Group, excellent infrastructural Department Neuroscience Regenerative Medicine, Medical College Georgia Augusta University (all YI). article presented scientific meeting [American Society Neurochemistry (ASN 2023 annual meeting)] March 19, Lexington, USA. C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Language: Английский

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Potential roles of gangliosides in chemical-induced neurodegenerative diseases and mental health disorders

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: April 22, 2024

Potential roles of gangliosides in chemical-induced neurodegenerative diseases and mental health disorders

Language: Английский

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The good, the bad, and the unknown nature of decreased GD3 synthase expression

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Nov. 22, 2024

This paper explores the physiological consequences of decreased expression GD3 synthase (GD3S), a biosynthetic enzyme that catalyzes synthesis b-series gangliosides. GD3S is key factor in tumorigenesis, with overexpression enhancing tumor growth, proliferation, and metastasis various cancers. Hence, inhibiting activity has potential therapeutic effects due to its role malignancy-associated pathways across different cancer types. also been investigated as promising target treatment neurodegenerative disorders. Drugs targeting have extensively explored underwent clinical trials, however mouse models, human subjects, vitro studies demonstrated serious adverse effects. We highlight these negative show original mass spectrometry imaging (MSI) data indicating inactivated can generally negatively affect energy metabolism, regulatory pathways, mitigation oxidative stress. The disturbance several systems induced by inhibition underscores vital this maintaining cellular homeostasis should be taken into account when considered target.

Language: Английский

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