Abstract
Lipid metabolism is drastically dysregulated in amyotrophic lateral sclerosis and impacts prognosis of patients. Animal models recapitulate alterations in the energy metabolism, including hypermetabolism and severe loss of adipose tissue. To gain insight into the molecular mechanisms underlying disease progression in amyotrophic lateral sclerosis, we have performed RNA-sequencing and lipidomic profiling in spinal cord of symptomatic SOD1G86R mice. Spinal transcriptome of SOD1G86R mice was characterized by differential expression of genes related to immune system, extracellular exosome, and lysosome. Hypothesis-driven identification of metabolites showed that lipids, including sphingomyelin(d18:0/26:1), ceramide(d18:1/22:0), and phosphatidylcholine(o-22:1/20:4) showed profound altered levels. A correlation between disease severity and gene expression or metabolite levels was found for sphingosine, ceramide(d18:1/26:0), Sgpp2, Sphk1, and Ugt8a. Joint-analysis revealed a significant enrichment of glycosphingolipid metabolism in SOD1G86R mice, due to the down-regulation of ceramide, glucosylceramide, and lactosylceramide and the overexpression of genes involved in their recycling in the lysosome. A drug-gene interaction database was interrogated to identify potential drugs able to modulate the dysregulated genes from the signaling pathway. Our results suggest that complex lipids are pivotally changed during the first phase of motor symptoms in an animal model of amyotrophic lateral sclerosis.
Highlights
Amyotrophic lateral sclerosis (ALS) is a non-cell autonomous disease characterized by a severe muscle denervation and degeneration of upper and lower motor neurons
ALS is a fatal condition characterized by degeneration of motor neurons
Several lines of evidence suggest that gene expression and lipid metabolism are differentially regulated in ALS, and could contribute to disease progression
Summary
Amyotrophic lateral sclerosis (ALS) is a non-cell autonomous disease characterized by a severe muscle denervation and degeneration of upper and lower motor neurons. Transgenic mice harboring mutations in the Sod gene are used as models of ALS, such as the SOD1G93A and the SOD1G86R models They recapitulate the main symptoms of ALS, including motor neuron degeneration, muscle denervation associated with severe paralysis and death (Ripps et al, 1995). We have recently reported that almost all lipid classes (e.g., triglycerides, phospholipids, sphingolipids) were strongly dysregulated at both presymptomatic and late disease stages, with metabolites showing either with an upregulation or downregulation in the spinal cord of SOD1G86R mice (Henriques et al, 2015b). We present for the first time an integrated analysis of RNA-sequencing and lipidomic data from the spinal cord of symptomatic SOD1G86R mice These results allow an unbiased vision of the metabolic changes in the course of ALS, and pinpoint specific pathways which are pathologically important
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