Myelin Abnormalities in the Optic and Sciatic Nerves in Mice With GM1-Gangliosidosis

Abstract

GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old β-galactosidase (β-gal) +/? and β-gal −/− mice, a model of GM1gangliosidosis. Optic nerve weight was lower in the β-gal −/− mice than in unaffected β-gal +/? mice, but no difference was seen in sciatic nerve weight. The levels of GM1 and GA1 were significantly increased in both the optic nerve and sciatic nerve of the β-gal −/− mice. The content of myelin-enriched cerebrosides, sulfatides, and plasmalogen ethanolamines was significantly lower in optic nerve of β-gal −/− mice than in β-gal +/? mice; however, cholesteryl esters were enriched in the β-gal −/− mice. No major abnormalities in these lipids were detected in the sciatic nerve of the β-gal −/− mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal −/− mice correlated with a reduction in the relative amount of myelin and periodicity in fresh nerve. By contrast, the relative amount of myelin and periodicity in the sciatic nerves from control and β-gal −/− mice were indistinguishable, suggesting minimal pathological involvement in sciatic nerve. Our results indicate that the greater neurochemical pathology observed in the optic nerve than in the sciatic nerve of β-gal −/− mice is likely due to the greater glycolipid storage in optic nerve.

Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain

“…Interestingly, pharmacological supplementation of PD patients with GM1a has been shown to have beneficial effects on clinical motor and neuropsychological functions in a 5-year study ( Schneider et al, 2010 ). Curiously, in addition to having essential functions in membrane lipid rafts ( Schnaar, 2016 ), GM1a is enriched in myelin ( Heinecke et al, 2015 ) and the GM1a increase observed here may reflect age-related changes in myelin structures.…”

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

“…An increase in G M1 and G A1 was found in the CNS of the current Glb1 −/− mice as well as in the CNS [24,58], optic and sciatic nerves [126] and in the retina [125] of other Glb1 knockout mouse models. Moreover, the increase in phosphatidylserine in the CNS of the current Glb1 −/− mice resembles the findings of Heinecke et al (2015) in the optic nerve [126]. Nevertheless, current Glb1 −/− mice also revealed accumulations of sphingomyelin and phosphatidylcholine, which might stabilize cell membrane integrity.…”

GM1 Gangliosidosis: Mechanisms and Management

“…Recent literature has addressed the role of myelin pathology in GM1 and other neuropathic LSDs. Studies involving children, 24,126,128 dogs, 144 mice, 145 and cats 146 with GM1 have universally reported decreased myelin in the CNS, with a reduction in Luxol Fast Blue staining being the most commonly reported evidence of this pathology. 24,126,146 Some studies have measured myelin using X-ray diffraction 145 or noted ultrastructural abnormalities with transmission electron microscopy (TEM) such as fewer myelinated axons 126 and unraveling of myelin sheaths (Figure 1A and B).…”

“…Studies involving children, 24,126,128 dogs, 144 mice, 145 and cats 146 with GM1 have universally reported decreased myelin in the CNS, with a reduction in Luxol Fast Blue staining being the most commonly reported evidence of this pathology. 24,126,146 Some studies have measured myelin using X-ray diffraction 145 or noted ultrastructural abnormalities with transmission electron microscopy (TEM) such as fewer myelinated axons 126 and unraveling of myelin sheaths (Figure 1A and B). 146 The mechanism(s) behind myelin abnormalities and their effects on disease pathogenesis is an emerging discussion topic in the literature, with three main hypotheses considered: dysmyelinogenesis (failure to form myelin properly), primary demyelination (dysfunction or destruction of myelin after proper formation), or secondary demyelination (due to axonal degeneration).…”