Gangliosides as apoptotic signals in ER stress response

d’Azzo, Alessandra; Tessitore, Alessandra; Sano, Renata

doi:10.1038/sj.cdd.4401834

Cited by 78 publications

(60 citation statements)

References 94 publications

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“…Gangliosides are important constituents of cell-membranes and are associated with a plethora of biological functions, including cellular recognition and adhesion, signal transduction, growth regulation and differentiation (Yu et al, 2004, d'Azzo et al, 2006. Structurally, gangliosides are glycosphingolipids that contain one or more sialic acid residues and are biosynthetically derived from lactosylceramide (Svennerholm and Raal, 1961, Ledeen, 1966, Svennerholm, 1980, Yu et al, 2004.…”

Section: Discussionmentioning

confidence: 99%

Glycolipid and ganglioside metabolism imbalances in Huntington's disease

Desplats

Denny

Kass

et al. 2007

Neurobiology of Disease

126

120

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We have explored genome-wide expression of genes related to glycobiology in exon 1 transgenic Huntington's disease (HD) mice using a custom designed GLYCOv2 chip and Affymetrix microarray analyses. We validated, using quantitative real-time PCR, abnormal expression levels of genes encoding glycosyltransferases in the striatum of R6/1 transgenic mice, as well as in postmortem caudate from human HD patients. Many of these genes show differential regional expression within the CNS, as indicated by in situ hybridization analysis, suggesting region-specific regulation of this system in the brain. We further show disrupted patterns of glycolipids (acidic and neutral lipids) and/ or ganglioside levels in both the forebrain of the R6/1 transgenic mice and caudate samples from human HD subjects. These findings reveal novel disruptions in glycolipid/ganglioside metabolic pathways in the pathology of HD and suggest that the development of new targets to restore glycosphingolipid balance may act to ameliorate some symptoms in HD.

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Section: Discussionmentioning

confidence: 99%

Glycolipid and ganglioside metabolism imbalances in Huntington's disease

Desplats

Denny

Kass

et al. 2007

Neurobiology of Disease

126

120

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“…25 Several gangliosides, among which GM2, GD3, GM3 and GD2 have been reported elevated in the white matter of patients suffering from various leukodystrophies, including MLD and Krabbe disease. 26,27 Similarly, ARSA knockout mice accumulate GM2 and GD3 gangliosides.…”

Section: Discussionmentioning

confidence: 99%

“…[28][29][30] GD3 is usually expressed at high levels in activated microglia and reactive astrocytes. 25 It is possible that the accumulation of gangliosides and other unidentified metabolites could also impair the trafficking of lysosomes from neuronal somata to the axonal and dendritic synapses. 21,31 A decrease in GM2 content was observed in ARSA knockout mice treated at an early stage (30% decrease) or at the symptomatic stage (15%), but this was probably not sufficient to reach a therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

et al. 2006

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Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

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“…Furthermore, gangliosides are key modulators of intracellular calcium flux. It has been hypothesized that ganglioside accumulation influences the endoplasmic reticulum calcium homeostasis thus contributing to the occurrence of apoptosis [79]. This could be of relevance in consideration of the recently assumed role of ER (ER stress) [80] in the apoptotic process.…”

Section: Raft-like Microdomains On Mitochondriamentioning

confidence: 99%

“…In this regard, the role of a close association of the ER with mitochondria in apoptosis regulation has recently been suggested [81,82]. In addition, the possible role of gangliosides in organelle scrambling processes has also to be taken into account [79].…”

Section: Raft-like Microdomains On Mitochondriamentioning

confidence: 99%

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

et al. 2007

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Several investigations have been carried out since many years in order to precisely address the function of lipid rafts in cell life and death. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides, sphingomyelin, cholesterol and signaling proteins, a plethora of possible interactions with various subcellular structures has been suggested. Their structural and functional role at the plasma membrane as well as in cell organelles such as endoplasmic reticulum and Golgi apparatus has been analyzed in detail in several studies. In particular, a specific activity of lipid rafts has been hypothesized to contribute to cell death by apoptosis. Although detected in various cell types, the role of lipid rafts in apoptosis has however been mostly studied in lymphocytes where the physiological apoptotic program occurs after CD95/Fas triggering. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation are summarized. Particular attention has been given to the mitochondrial raft-like microdomains, which may represent preferential sites where some key reactions can take place and can be catalyzed, leading to either survival or death of T cells.

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Gangliosides as apoptotic signals in ER stress response

Cited by 78 publications

References 94 publications

Glycolipid and ganglioside metabolism imbalances in Huntington's disease

Glycolipid and ganglioside metabolism imbalances in Huntington's disease

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

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