Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase
| Autor: | Michael Spedding, Ghulam Hussain, Jose-Luis Gonzalez de Aguilar, Jean-Philippe Loeffler, Sylvie Dirrig-Grosch, Claire Boursier-Neyret, Vincent Croixmarie, Angela Rosenbohm, Eleonora D'Ambra, Mylene Huebecker, Andoni Echaniz-Laguna, Albert C. Ludolph, Alexandre Henriques, Bernard Walther, David A. Priestman, Frances M. Platt |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Blotting Western SOD1 Biology Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Genetics medicine Animals Humans Amyotrophic lateral sclerosis Molecular Biology Chromatography High Pressure Liquid Genetics (clinical) Retrospective Studies 030304 developmental biology Denervation Sphingolipids 0303 health sciences Electromyography Reverse Transcriptase Polymerase Chain Reaction Amyotrophic Lateral Sclerosis Skeletal muscle Lipid metabolism Articles General Medicine Nerve injury medicine.disease Sphingolipid Endocrinology medicine.anatomical_structure Biochemistry Glucosyltransferases Peripheral nerve injury medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddv439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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