title: Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701; jim.dodge@genzyme.com richard_sidman@hms.harvard.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Joshua
authors.initials: J
authors.lastname: Pacheco
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Samantha
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Channa
authors.initials: C
authors.lastname: Bao
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Marissa
authors.initials: M
authors.lastname: Abraham
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Mandy
authors.initials: M
authors.lastname: Cromwell
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: S Pablo
authors.initials: SP
authors.lastname: Sardi
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 jim.dodge@genzyme.com richard_sidman@hms.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Rare Diseases Science, Genzyme, a Sanofi Company, Framingham, MA 01701;
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005679:G(M3) Ganglioside / Q000008:administration & dosage; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006028:Glycosphingolipids / Q000502:physiology*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013116:Spinal Cord / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D005679:G(M3) Ganglioside; D006028:Glycosphingolipids; D013482:Superoxide Dismutase; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
keywords: FALS; SALS; motor neuron disease; mouse models neurological disease