Inhibition of \u03b2-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Alexandre Henriques,David A Priestman,Frances M Platt,Mylene Huebecker,Céline Keime,Michael Spedding,Jean-Philippe Loeffler,Hélène Blasco,Philippe Corcia,Christian R Andres

doi:10.1038/s41598-017-05313-0

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.

Highlights

Uses lipids preferentially over carbohydrates as nutrients[11], and survives longer when fed with a high fat diet[12]
Altered ganglioside expression is evident at disease onset in SOD1G86R mice and ALS patients
We sought to determine whether disease progression could be associated with loss of GM1a at the neuromuscular junctions (NMJs) in an animal model of ALS, the SOD1G86R mouse

Summary

Introduction

Uses lipids preferentially over carbohydrates as nutrients[11], and survives longer when fed with a high fat diet[12]. Changes in levels of sphingolipids, of glycosphingolipids, were recently described in the central nervous system of ALS patients at disease endpoint and in SOD1 mice at various disease stages[13, 14]. We have shown recently that NMJ integrity in SOD1G86R mice requires functional synthesis of glucosylceramide, the precursor of more complex glycosphingolipids, suggesting that they could be key modulators of ALS severity[13, 14]. High dose CBE (100 mg/kg/d) has been used to inhibit the lysosomal GCase almost completely in neonatal mice to induce a chemical model of Gaucher’s diseases with neuronal toxicity[27, 28]. We studied the metabolism of glycosphingolipids in ALS at early disease stage, in patients and in SOD1G86R mice, and its relation to the integrity of NMJs

Methods

Results

Conclusion