Biology subjects

Itokazu, Y.

Publications and source records attributed to Itokazu, Y..

3 recordsLinked to original sources

bioRxiv2025

GM1 and GD3 Gangliosides Attenuate NGF-TrkA and BDNF-TrkB Signaling Dysfunction Associated with Acute Diisopropylfluorophosphate Exposure in Mouse Brain

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single toxic dose of the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, seven days of repeated intranasal administration of gangliosides GM1 or GD3 24 hours after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 can prevent the organophosphate-related alterations in those brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological deficits associated with a class of poisons that endangers millions of people worldwide. Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646417v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@edf17dorg.highwire.dtl.DTLVardef@1895982org.highwire.dtl.DTLVardef@538e99org.highwire.dtl.DTLVardef@1b700d3_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIA single exposure to DFP, which causes cognitive deficits, dysregulates NGF and BDNF signaling C_LIO_LIGM1 or GD3 24 hours after DFP injection prevents the alteration of the neurotrophin signaling C_LIO_LIIntranasal ganglioside treatment provides neuroprotective effects against persistent organophosphate toxicity C_LI

pharmacology and toxicology↗

bioRxiv2024

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

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

neuroscience↗

bioRxiv2023

Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis

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 the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogenous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent upon their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3-synthase knockout (GD3S-KO) mouse brains. The specific roles of GD3 in determining the stage and cell-lineage determination of NSCs remain unclear, since global GD3S-KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here we show that inducible GD3 deletion in postnatal radial glia-like NSCs promotes the NSC activation, resulting in the loss of the long-term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S-conditional-knockout mice led to impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia-like NSCs in the adult NSC niche. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/532547v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@15a6451org.highwire.dtl.DTLVardef@1702776org.highwire.dtl.DTLVardef@2edbb1org.highwire.dtl.DTLVardef@59822f_HPS_FORMAT_FIGEXP M_FIG C_FIG Main PointsO_LIRadial glia-like neural stem cells (RGLs) lacking GD3 promote activation of quiescent RGLs. C_LIO_LIPostnatal depletion of GD3 results in reduced neural stem cell pools and impaired adult neurogenesis. C_LIO_LIPostnatal GD3 deletion in RGLs leads to impairment of olfactory and memory functions. C_LI

neuroscience↗