Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis.
Fiche publication
Date publication
juillet 2017
Journal
Scientific reports
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LOEFFLER Jean-Philippe
Tous les auteurs :
Henriques A, Huebecker M, Blasco H, Keime C, Andres CR, Corcia P, Priestman DA, Platt FM, Spedding M, Loeffler JP
Lien Pubmed
Résumé
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 SOD1(G86R) 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.
Mots clés
Aged, Amyotrophic Lateral Sclerosis, physiopathology, Animals, Case-Control Studies, Disease Models, Animal, Female, Glucosylceramidase, antagonists & inhibitors, Glycosphingolipids, metabolism, Humans, Male, Mice, Mice, Knockout, Motor Neurons, physiology, Neuromuscular Junction, physiology, PC12 Cells, Rats, Signal Transduction, Spinal Cord, physiology, Superoxide Dismutase, physiology
Référence
Sci Rep. 2017 Jul;7(1):5235