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.