Nucleocytosolic transport, a membrane process, is impaired in motor neurons in 
amyotrophic lateral sclerosis (ALS). This study analyzes the nuclear lipidome in 
motor neurons in ALS and examines molecular pathways linked to the major lipid 
alterations. Nuclei were obtained from the frozen anterior horn of the lumbar 
spinal cord of ALS patients and age-matched controls. Lipidomic profiles of this 
subcellular fraction were obtained using liquid chromatography and mass 
spectrometry. We validated the mechanisms behind presumable lipidomic changes by 
exploring ALS surrogate models including human motor neurons (derived from ALS 
lines and controls) subjected to oxidative stress, the hSOD-G93A transgenic 
mice, and samples from an independent cohort of ALS patients. Among the 
differential lipid species, we noted 41 potential identities, mostly belonging 
to phospholipids (particularly ether phospholipids, as plasmalogens), as well as 
diacylglycerols and triacylglycerides. Decreased expression of 
alkyldihydroxyacetonephosphate synthase (AGPS)-a critical peroxisomal enzyme in 
plasmalogen synthesis-is found in motor neuron disease models; this occurs in 
parallel with an increase in the expression of sterol carrier protein 2 (SCP2) 
mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified 
diminished expression of diacylglycerol-related enzymes, such as phospholipase C 
βI (PLCβI) and protein kinase CβII (PKCβII), linked to diacylglycerol 
metabolism. Finally, lipid droplets were recognized in the nuclei, supporting 
the identification of triacylglycerides as differential lipids. Our results 
point to the potentially pathogenic role of altered composition of nuclear 
membrane lipids and lipids in the nucleoplasm in the anterior horn of the spinal 
cord in ALS. Overall, these data support the usefulness of subcellular 
lipidomics applied to neurodegenerative diseases.