Ganglioside patterns in human spinal cord

Vorwerk, CK

doi:10.1038/sj.sc.3101232

Cited by 3 publications

(2 citation statements)

References 35 publications

(21 reference statements)

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“…To determine whether GSL levels are modified in the spinal cords of ALS patients, we examined cervical spinal tissue samples collected at autopsy from six male ALS patients and six age-matched male controls. In contrast to earlier studies that examined total GSL levels in the whole spinal cord (10), we analyzed gray matter (GM) and ventral white matter (VWM) samples separately, because regional variation in total ganglioside levels within segments of spinal cord have previously been reported (24). We also measured individual molecular isoforms of GSLs because of their distinct biological functions (25).…”

Section: Gsl Levelsmentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

141

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Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1 G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1 G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2-9)-all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine...

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Section: Gsl Levelsmentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

141

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“…Interestingly, the ganglioside profile of a subject changes with age. In an adult spinal cord, GD1b and GD3 are among the most prevalent gangliosides throughout the anterior and posterior regions of both the cervical and lumbar spinal cord [12]. The total concentration of GM2 and GM3 ganglioside is less than 5%.…”

Section: Gangliosidesmentioning

confidence: 98%

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Ryckman

Brockhausen

Walia

2020

IJMS

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Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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