Ganglioside rafts as MAG receptors that mediate blockade of axon growth

McKerracher, Lisa

doi:10.1073/pnas.132280299

Cited by 42 publications

(36 citation statements)

References 29 publications

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“…Sphingolipids regulate a wide variety of neurobiologic processes, including neurotropic signaling, 22 neural cell adhesion and migration, 23,24 synaptic transmission/axonal guidance, 23,25 and neuron-glial interactions. 26 Sphingolipids regulate these (and other) biological functions by affecting the biophysical properties of membranes, and through lipid-protein interactions that control protein location, scaffolding, and posttranslational modifications. In a previous cross-sectional study, we found that both ceramide and sphingomyelin species (C18 and C24) were elevated in CSF of HIVpositive subjects with cognitive impairment.…”

Section: (Sd)mentioning

confidence: 99%

A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects

et al. 2013

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Objective: In this multicenter cohort study, we sought to identify prognostic and associative metabolic indicators for HIV-associated neurocognitive disorders (HAND).Methods: A quantitative lipidomic analysis was conducted on 524 longitudinal CSF samples collected from 7 different performance sites across the mainland United States, Hawaii, and Puerto Rico. Subjects included HIV-infected individuals with longitudinal clinical and cognitive testing data and cognitively normal HIV-negative healthy controls.Results: At baseline, HIV1 subjects could be differentiated from HIV2 controls by reductions in a single ceramide species and increases in multiple forms of cholesterol. Perturbations in cholesterol metabolism and ceramide were influenced by combined antiretroviral therapy (cART) use. There were no cross-sectional baseline differences in any lipid metabolite when HIV1 subjects were grouped according to cognitive status. However, a single sphingolipid metabolite and reduced levels of esterified cholesterols were prognostic indicators of incident cognitive decline. Longitudinal patterns of these disturbances in sphingolipid and sterol metabolism suggest that a progressive disorder of lipid metabolism that is similar to disorders of lipid storage may contribute to the pathogenesis of HAND.Conclusions: These findings suggest that HIV infection and cART are independently associated with a CNS metabolic disturbance, identify surrogate markers that are prognostic for cognitive decline, and implicate a lipid storage-like disorder in the progression of HAND. The widespread use of combined antiretroviral therapy (cART) in developed countries has dramatically decreased the death rates due to AIDS and decreased the incidence of dementia. 1,2However, cART has not reduced the prevalence rates for milder forms of HIV-associated neurocognitive disorders (HAND) that are associated with increased mortality.3-6 HAND frequently manifests in the domains of memory and executive functions, 7 and is associated with decreased adherence to pharmacotherapy, lower cognitive reserve, and increased incidence of psychiatric comorbidities. 8,9 Despite cART, there is evidence for ongoing neurologic damage that includes persistent astrocyte infection, brain volume loss, inflammation, synaptodendritic damage, and disruptions in white matter integrity. 5,[10][11][12] The mechanisms underlying these residual neuropathologic impairments remain obscure.Several studies have suggested that dysregulations in CNS lipid metabolism may be involved in the pathogenesis of HAND. [13][14][15] In particular, roles for ceramides, sphingomyelins, and cholesterol have been described, but the interrelationships of these bioactive lipids to the temporal progression *These authors contributed equally to this work.

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Section: (Sd)mentioning

confidence: 99%

A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects

et al. 2013

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“…SL, together with many classes of proteins involved in mechanisms of signal transduction that are relevant for neural cell biology, such as (1) receptor tyrosine kinases (including neurotrophin receptors Trk A, Trk B, Trk C, c-Ret, ErbB, the ephrin receptor Eph), GPI-anchored receptors (the GDNF family receptor GFRα), G protein-coupled receptors (including cannabinoid receptors and neurotransmitter receptors such as α1-, β1-, β2-adrenergic, adenosine A1, γ-aminobutyric acid GABAb, muscarinic M2, glutamate metabotropic mGLUR, serotonin 5HT2), (2) non-receptor tyrosine kinases of the Src family, (3) adapter and regulatory molecules of tyrosine kinase signaling, (4) heterotrimeric and small GTP-binding proteins, (5) protein kinase C isoenzymes, (6) cell adhesion molecules, including integrins, Notch1, NCAMs, TAG-1, Thy-1, F3/contactin, (7) ion channels, proteins involved in neurotransmitter release, postsynaptic density complex proteins [92,93,[147][148][149][150][151][152][153][154][155] segregate in lipid rafts present in cultured neural cells (neurons, oligodendrocytes, astrocytes, and neurotumoral cell lines), as well as in different brain regions, myelin, and synaptic plasma membranes. This particular clustering affects neurotrophic factor signaling [147,148,151,152], cell adhesion and migration [147,156,157], axon guidance, synaptic transmission [147,158], neuron-glia interactions [159,160], and myelin genesis [161].…”

Section: Neuron-glia Interactions (Myelination)mentioning

confidence: 99%

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

et al. 2010

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Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

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“…A physiological regulatory role of SL, and in particular of gangliosides, has been documented for biological events of great relevance for neural cell biology, such as neurotrophic factor signaling [55-58], neural cell adhesion and migration [56, 59,60], axon guidance, synaptic transmission [56, 61], neuron-glia interactions [62,63] and myelin genesis [64]. The ability of SL to modulate the activity of plasma membrane proteins via direct or lipid rafts-mediated lateral interactions can explain the multiple roles of SL in regulating these cellular functions [65][66][67].…”

Section: Sphingolipids In Nervous System Physiology and Pathologymentioning

confidence: 99%

Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases

et al. 2011

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In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal membrane sphingolipid patterns and altered plasma membrane organization. In this paper, we review the potential importance of these alterations to the pathogenesis of these diseases and focus the reader's attention on some secondary alterations of sphingolipid metabolism that have been sporadically reported in the literature. Moreover, we present a detailed analysis of the lipid composition of different central nervous system and extraneural tissues from the acid sphingomyelinase-deficient mouse, the animal model for Niemann-Pick disease type A, characterized by the accumulation of sphingomyelin. Our data show an unexpected, tissue specific selection of the accumulated molecular species of sphingomyelin, and an accumulation of GM3 and GM2 gangliosides in both neural and extraneural tissues, that cannot be solely explained by the lack of acid sphingomyelinase.

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Ganglioside rafts as MAG receptors that mediate blockade of axon growth

Cited by 42 publications

References 29 publications

A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects

A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases

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