Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase.
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets.
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.
Alexandre
A
Henriques
Technologie Servier, Orleans, France.
Vincent
V
Croixmarie
Department of Pharmacology, University of Oxford, Oxford, UK.
David A
DA
Priestman
Department of Neurology, University of Ulm, Ulm, Germany.
Angela
A
Rosenbohm
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.
Sylvie
S
Dirrig-Grosch
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.
Eleonora
E
D'Ambra
Department of Pharmacology, University of Oxford, Oxford, UK.
Mylene
M
Huebecker
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France, Department of Physiology, GC University, Faisalabad, Pakistan.
Ghulam
G
Hussain
Technologie Servier, Orleans, France.
Claire
C
Boursier-Neyret
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France, Hôpitaux Universitaires, Département de Neurologie, Strasbourg, France.
Andoni
A
Echaniz-Laguna
Department of Neurology, University of Ulm, Ulm, Germany.
Albert C
AC
Ludolph
Department of Pharmacology, University of Oxford, Oxford, UK.
Frances M
FM
Platt
Technologie Servier, Orleans, France.
Bernard
B
Walther
Les Laboratoires Servier, Suresnes, France and Spedding Research Solutions SARL, Le Vesinet, France.
Michael
M
Spedding
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.
Jean-Philippe
JP
Loeffler
Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France, gonzalez@unistra.fr.
Jose-Luis
JL
Gonzalez De Aguilar
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004576:Electromyography; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism*
D013107:Sphingolipids; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase