Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis

Furukawa, Koichi; Ohmi, Yuhsuke; Ji, Shuting; Zhang, Pu; Bhuiyan, Robiul H.; Ohkawa, Yuki; Tajima, Orie; Hashimoto, Noboru

doi:10.1016/j.bbagen.2017.06.007

Cited by 23 publications

(17 citation statements)

References 30 publications

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“…Moreover, we also found a normal localization of the variant ST3GAL5s. Altogether, this data is in agreement with the current hypothesis that the total absence of gangliosides is responsible for the general lack of neuron homeostasis, leading to inflammation and, consequently, loss of several functions [105]. However, many patients present mildly elevated blood lactate and their cells have an impaired respiratory chain function [25,100].…”

Section: Specific Diseases Of Ganglioside Biosynthesis Determiningsupporting

confidence: 89%

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Indellicato

Trinchera

2019

IJMS

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Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

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Section: Specific Diseases Of Ganglioside Biosynthesis Determiningsupporting

confidence: 89%

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Indellicato

Trinchera

2019

IJMS

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“…Glycosphingolipids are enriched in glycolipid-enriched microdomain (GEM)/rafts on the plasma membrane of various cells [27], and enhance or attenuate the cell signals in the GEM/rafts [3,28,29,30,31]. Gb4 may also be localized in GEM/rafts, and interact with membrane molecules such as receptors, resulting in the formation of molecular complexes in the GEM/rafts, and promote the proliferation and/or differentiation of osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Glycosphingolipids are considered to play an important role in the development and maintenance of various organs and tissues [1,2,3]. These have also been shown to be critical for protection against inflammation and degeneration [4].…”

Section: Introductionmentioning

confidence: 99%

Deletion of Gb3 Synthase in Mice Resulted in the Attenuation of Bone Formation via Decrease in Osteoblasts

Hamamura

Hamajima

et al. 2019

IJMS

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Glycosphingolipids are known to play a role in developing and maintaining the integrity of various organs and tissues. Among glycosphingolipids, there are several reports on the involvement of gangliosides in bone metabolism. However, there have been no reports on the presence or absence of expression of globo-series glycosphingolipids in osteoblasts and osteoclasts, and the involvement of their glycosphingolipids in bone metabolism. In the present study, we investigated the presence or absence of globo-series glycosphingolipids such as Gb3 (globotriaosylceramide), Gb4 (globoside), and Gb5 (galactosyl globoside) in osteoblasts and osteoclasts, and the effects of genetic deletion of Gb3 synthase, which initiates the synthesis of globo-series glycosphingolipids on bone metabolism. Among Gb3, Gb4, and Gb5, only Gb4 was expressed in osteoblasts. However, these glycosphingolipids were not expressed in pre-osteoclasts and osteoclasts. Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in Gb3 synthase-knockout (Gb3S KO) mice was lower than that in wild type (WT) mice. Calcein double labeling also revealed that bone formation in Gb3S KO mice was significantly lower than that in WT mice. Consistent with these results, the deficiency of Gb3 synthase in mice decreased the number of osteoblasts on the bone surface, and suppressed mRNA levels of osteogenic differentiation markers. On the other hand, osteoclast numbers on the bone surface and mRNA levels of osteoclast differentiation markers in Gb3S KO mice did not differ from WT mice. This study demonstrated that deletion of Gb3 synthase in mice decreases bone mass via attenuation of bone formation.

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“…Gangliosides, which are sialic-acid-containing glycosphingolipids, are highly expressed in the nervous tissues of vertebrates [1] and have been considered as being involved in the regulation of nervous systems [2,3,4,5]. Recent studies of mutant mice lacking various gangliosides have revealed that gangliosides are essential in the maintenance of the integrity of nervous tissues and spermatogenesis, as well as the homeostasis of organisms [6,7,8]. GM3-only mice (double knockout mice lacking GM2/GD2 synthase and GD3 synthase genes) have exhibited severe neurodegeneration caused by excessive complement activation in the brain and spinal cord [9,10].…”

Section: Introductionmentioning

confidence: 99%

Deficiency of GD3 Synthase in Mice Resulting in the Attenuation of Bone Loss with Aging

Hamamura

Mishima

et al. 2019

IJMS

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Gangliosides are widely expressed in almost all tissues and cells and are also considered to be essential in the development and maintenance of various organs and tissues. However, little is known about their roles in bone metabolism. In this study, we investigated the effects of genetic deletion of ganglioside D3 (GD3) synthase, which is responsible for the generation of all b-series gangliosides, on bone metabolism. Although b-series gangliosides were not expressed in osteoblasts, these gangliosides were expressed in pre-osteoclasts. However, the expression of these gangliosides was decreased after induction of osteoclastogenesis by receptor activator of nuclear factor kappa-B ligand (RANKL). Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in GD3 synthase-knockout (GD3S KO) mice was higher than that in wild type (WT) mice at the age of 40 weeks, although there were no differences in that between GD3S KO and WT mice at 15 weeks old. Whereas bone formation parameters (osteoblast numbers/bone surface and osteoblast surface/bone surface) in GD3S KO mice did not differ from WT mice, bone resorption parameters (osteoclast numbers/bone surface and osteoclast surface/bone surface) in GD3S KO mice became significantly lower than those in WT mice at 40 weeks of age. Collectively, this study demonstrates that deletion of GD3 synthase attenuates bone loss that emerges with aging.

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Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis

Cited by 23 publications

References 30 publications

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Deletion of Gb3 Synthase in Mice Resulted in the Attenuation of Bone Formation via Decrease in Osteoblasts

Deficiency of GD3 Synthase in Mice Resulting in the Attenuation of Bone Loss with Aging

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