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Xuntian Jiang - One of the best experts on this subject based on the ideXlab platform.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
Hua Cheng - One of the best experts on this subject based on the ideXlab platform.
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apolipoprotein e mediates sulfatide depletion in animal models of alzheimer s disease
Neurobiology of Aging, 2010Co-Authors: Hua Cheng, Yunhua Zhou, David M HoltzmanAbstract:Abstract Herein, we tested a recently proposed working model of apolipoprotein E (apoE)-mediated sulfatide metabolism/trafficking/homeostasis with two well-characterized amyloid precursor protein (APP) transgenic (Tg) animal models of Alzheimer's disease (AD) (i.e., APPV717F and APPsw) on a wild-type murine apoE background or after being bred onto an Apoe−/− background. As anticipated, lipidomics analysis demonstrated that the sulfatide levels in brain tissues were reduced beginning at approximately 6 months of age in APPV717F Tg, Apoe+/+ mice and at 9 months of age in APPsw Tg, Apoe+/+ mice relative to their respective non-APP Tg littermates. This reduction increased in both APP Tg mice as they aged. In contrast, sulfatide depletion did not occur in APP Tg, Apoe−/− animals relative to the Apoe−/− littermates. The lack of sulfatide depletion in APP Tg, Apoe−/− mice strongly supports the role of apoE in the deficient sulfatide content in APP Tg, Apoe+/+ mice. Collectively, through different animal models of AD, this study provides evidence for an identified biochemical mechanism that may be responsible for the sulfatide depletion at the earliest stages of AD.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
Youchun Zeng - One of the best experts on this subject based on the ideXlab platform.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
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endosomes and lysosomes play distinct roles in sulfatide induced neuroblastoma apoptosis potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases
Biochemical Journal, 2008Co-Authors: Youchun Zeng, Hua Cheng, Xuntian JiangAbstract:Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer9s disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.
John Turk - One of the best experts on this subject based on the ideXlab platform.
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electrospray ionization tandem mass spectrometric analysis of sulfatide determination of fragmentation patterns and characterization of molecular species expressed in brain and in pancreatic islets
Biochimica et Biophysica Acta, 1998Co-Authors: Alan Bohrer, John TurkAbstract:Abstract The sphingolipid sulfatide is a component of myelin and some non-neuronal cells. Antibodies to sulfatide occur in some patients with autoimmune neuropathies and in patients with insulin-dependent diabetes mellitus (IDDM) caused by immunologic destruction of insulin-secreting pancreatic islet β-cells. Distinct sulfatide molecular species may differ in immunogenicity, and facile means to identify sulfatide species in islets and other tissues obtainable in only small amounts could be useful. Electrospray ionization mass spectrometry (ESI/MS) permits structural determination of small quantities of phospholipids and is applied here to sulfatide analysis. We find that sulfatide standards are readily analyzed by negative ion ESI/MS, and tandem mass spectra of individual species exhibit some ions common to all species and other ions that reflect distinct fatty acid substituents in different sulfatide molecules. A signature ion cluster resulting from cleavage directed by the α-hydroxy group of sulfatide species with a hydroxylated fatty acid substituent identifies such species. Sulfatide profiles in tissue lipid extracts can be obtained by ESI/MS/MS scanning for common sulfatide ions and for ions reflecting fatty acid substituents. Islets are demonstrated to contain sulfatide and to exhibit a profile of species different from that of brain.
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electrospray ionization tandem mass spectrometric analysis of sulfatide determination of fragmentation patterns and characterization of molecular species expressed in brain and in pancreatic islets
Biochimica et Biophysica Acta, 1998Co-Authors: Alan Bohrer, John TurkAbstract:Abstract The sphingolipid sulfatide is a component of myelin and some non-neuronal cells. Antibodies to sulfatide occur in some patients with autoimmune neuropathies and in patients with insulin-dependent diabetes mellitus (IDDM) caused by immunologic destruction of insulin-secreting pancreatic islet β-cells. Distinct sulfatide molecular species may differ in immunogenicity, and facile means to identify sulfatide species in islets and other tissues obtainable in only small amounts could be useful. Electrospray ionization mass spectrometry (ESI/MS) permits structural determination of small quantities of phospholipids and is applied here to sulfatide analysis. We find that sulfatide standards are readily analyzed by negative ion ESI/MS, and tandem mass spectra of individual species exhibit some ions common to all species and other ions that reflect distinct fatty acid substituents in different sulfatide molecules. A signature ion cluster resulting from cleavage directed by the α-hydroxy group of sulfatide species with a hydroxylated fatty acid substituent identifies such species. Sulfatide profiles in tissue lipid extracts can be obtained by ESI/MS/MS scanning for common sulfatide ions and for ions reflecting fatty acid substituents. Islets are demonstrated to contain sulfatide and to exhibit a profile of species different from that of brain.
Dick Hoekstra - One of the best experts on this subject based on the ideXlab platform.
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sulfatide mediated control of extracellular matrix dependent oligodendrocyte maturation
Glia, 2014Co-Authors: Wia Baron, Marjolein Bijlard, Anita Nomden, Jenny C De Jonge, Charlotte E Teunissen, Dick HoekstraAbstract:In the central nervous system, the extracellular matrix (ECM) compound laminin-2, present on developing axons, is essential in regulating oligodendrocyte (OLG) maturation. For example, laminin-2 is involved in mediating interactions between integrins and growth factors, initially localizing in separate membrane microdomains. The galactosphingolipid sulfatide is an important constituent of these microdomains and may serve as a receptor for laminin-2. Here, we investigated whether sulfatide interferes with ECM-integrin interactions and, in this manner, modulates OLG maturation. Our data reveal that disruption of laminin-2-sulfatide interactions impeded OLG differentiation and myelin-like membrane formation. On laminin-2, but not on (re)myelination-inhibiting fibronectin, sulfatide laterally associated with integrin alpha 6 in membrane microdomains. Sulfatide was partly excluded from membrane microdomains on fibronectin, thereby likely precluding laminin-2-mediated myelination. Anti-sulfatide antibodies disrupted integrin alpha 6-PDGF alpha R interactions on laminin-2 and induced demyelination in myelinated spheroid cultures, but intriguingly stimulated myelin-like membrane formation on fibronectin. Taken together, these findings highlight the importance of laminin-sulfatide interactions in the formation of functional membrane microdomains essential for myelination. Thus, laminin-sulfatide interactions might control the asynchronous localized differentiation of OLGs, thereby allowing myelination to be triggered by axonal demand. Given the accumulation of fibronectin in multiple sclerosis lesions, the findings also provide a molecular rationale for the potential of anti-sulfatide antibodies to trigger quiescent endogenous OLG progenitor cells in axon remyelination. GLIA 2014;62:927-942
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sulfatide mediated control of extracellular matrix dependent oligodendrocyte maturation
Glia, 2014Co-Authors: Wia Baron, Marjolein Bijlard, Anita Nomden, Jenny C De Jonge, Charlotte E Teunissen, Dick HoekstraAbstract:In the central nervous system, the extracellular matrix (ECM) compound laminin-2, present on developing axons, is essential in regulating oligodendrocyte (OLG) maturation. For example, laminin-2 is involved in mediating interactions between integrins and growth factors, initially localizing in separate membrane microdomains. The galactosphingolipid sulfatide is an important constituent of these microdomains and may serve as a receptor for laminin-2. Here, we investigated whether sulfatide interferes with ECM-integrin interactions and, in this manner, modulates OLG maturation. Our data reveal that disruption of laminin-2-sulfatide interactions impeded OLG differentiation and myelin-like membrane formation. On laminin-2, but not on (re)myelination-inhibiting fibronectin, sulfatide laterally associated with integrin alpha 6 in membrane microdomains. Sulfatide was partly excluded from membrane microdomains on fibronectin, thereby likely precluding laminin-2-mediated myelination. Anti-sulfatide antibodies disrupted integrin alpha 6-PDGF alpha R interactions on laminin-2 and induced demyelination in myelinated spheroid cultures, but intriguingly stimulated myelin-like membrane formation on fibronectin. Taken together, these findings highlight the importance of laminin-sulfatide interactions in the formation of functional membrane microdomains essential for myelination. Thus, laminin-sulfatide interactions might control the asynchronous localized differentiation of OLGs, thereby allowing myelination to be triggered by axonal demand. Given the accumulation of fibronectin in multiple sclerosis lesions, the findings also provide a molecular rationale for the potential of anti-sulfatide antibodies to trigger quiescent endogenous OLG progenitor cells in axon remyelination. GLIA 2014;62:927-942
