Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis - PubMed (original) (raw)

. 2015 Jun 30;112(26):8100-5.

doi: 10.1073/pnas.1508767112. Epub 2015 Jun 8.

Christopher M Treleaven 2, Joshua Pacheco 2, Samantha Cooper 2, Channa Bao 2, Marissa Abraham 2, Mandy Cromwell 2, S Pablo Sardi 2, Wei-Lien Chuang 2, Richard L Sidman 3, Seng H Cheng 2, Lamya S Shihabuddin 2

Affiliations

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

James C Dodge et al. Proc Natl Acad Sci U S A. 2015.

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.

Keywords: FALS; SALS; motor neuron disease; mouse models neurological disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

GSL accumulation is a neuropathological feature of disease in ALS patients. Major isoforms of Cer, Cerebroside, GalCer, GlcCer, LacCer, GL3, GM3, GM1, and SPM are significantly elevated (#P < 0.05, ϕ_P_ < 0.01, ♦P < 0.001, *P < 0.0001) in cervical spinal cord homogenates of ALS patients. Statistical comparisons shown are made to control (CTRL) tissue subtype. Minor isoform data and comparisons between different subtypes are reported in SI Appendix, Table S1. Error bars represent ± SEM.

Fig. 2.

Fig. 2.

ALS mice display complex changes in GSL levels within the spinal cord. Major isoforms of Cer, Cerebroside, GalCer, GlcCer, LacCer, GL3, GM3, GM1, and SPM are significantly altered (#P < 0.05, ϕ_P_ < 0.01, ♦P < 0.001, *P < 0.0001) in ALS mice vs. WT controls. Minor isoform data and comparisons between different phases of ALS disease are reported in SI Appendix, Table S2. Error bars represent ± SEM.

Fig. 3.

Fig. 3.

GSL metabolism is altered in the spinal cords of ALS patients and mice. (A) Lysosomal (pH 4.5) and cytoplasmic (pH = 7.0) GBA1, GBA2, HEX, GALC, α-GAL, and β-GAL activities in the cervical spinal cord homogenates of ALS patients and age-matched controls. Statistical comparisons are relative to CTRL tissue subtype (#P < 0.05, ϕ_P_ < 0.01). (B) Lysosomal enzyme activities measured in SYMP, ES, and MB ALS mice compared with WT controls. Groups not connected by the same letter are significantly different (P < 0.01). Error bars represent ± SEM.

Fig. 4.

Fig. 4.

Modulation of GSL levels impacts disease progression in ALS mice. (A) Inhibition of GSL synthesis within the CNS accelerates disease progression in ALS mice. ALS mice treated with GENZ-667161 (161) (inhibitor of glucosylceramide synthase with CNS penetrance) showed significant changes in the rate of body weight loss (*P < 0.01), the median onset of end stage (males = 104 vs. 118 d, females = 100.5 vs. 128.5 d; P < 0.0001), and median survival (males = 112 vs. 123 d, females = 121 vs. 132.5 d; P < 0.0001) vs. untreated ALS sibling/sex-matched counterparts. (B) The onset of paralysis was significantly (P < 0.0095) delayed by 8 d, and survival was significantly (P < 0.0473) extended by 6 d in ALS mice that received continuous intracerebroventricular infusion of GM3 (12 μg/d) vs. mice infused with vehicle (artificial cerebrospinal fluid) (treatment initiated at day 90).

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