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Sci Rep. 2017 Jul 12;7(1):5235. doi: 10.1038/s41598-017-05313-0.

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis.

Author information

1
Université de Strasbourg, UMR_S 1118, Fédération de Médecine Translationnelle, Strasbourg, France.
2
INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France.
3
Spedding Research Solutions SAS, Le Vesinet, France.
4
Department of Pharmacology, University of Oxford, Oxford, UK.
5
INSERM, Université François-Rabelais, U930, Neurogénétique et Neurométabolomique, Tours, France.
6
CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France.
7
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U964, CNRS, UMR7104, Université de Strasbourg, 67404, Illkirch, France.
8
CHRU de Tours, Centre SLA, Tours, France.
9
Université de Strasbourg, UMR_S 1118, Fédération de Médecine Translationnelle, Strasbourg, France. loeffler@unistra.fr.
10
INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France. loeffler@unistra.fr.

Abstract

Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

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