期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8100-8105
DOI：10.1073/pnas.1508767112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGlycosphingolipids are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide. Genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases. Here, we investigated whether alterations in glycosphingolipids contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). We show that ALS patients and model mice display disease-related changes in spinal cord glycosphingolipids levels and in the enzymes that regulate their metabolism. Importantly, we demonstrate that inhibition of glycosphingolipid synthesis in ALS model mice exacerbated disease progression, whereas administration of GM3, a subtype of glycosphingolipids, slowed it, thus implicating glycosphingolipids as potentially important participants in ALS pathogenesis and potential targets for future drug development. 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, -galactosidase, and {beta}-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A 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.
