Sphingolipid Synthesis

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Sphingolipids are crucial for myelination and neurite outgrowth and maturation, but their role as pathogenic factors in ADHD is still underexplored. Here, we present the first direct evidence supporting the association between variants in genes from the sphingolipid pathway and ADHD. Figure 1 shows a schematic representation of the sphingolipid metabolic pathway along with the genes encoding for the principal enzymes in sphingolipid biosynthesis. Genes identified by this study as significantly associated with ADHD susceptibility are highlithed. Briefly, ceramide is central in sphingolipid metabolism and is produced by de novo and recycling pathways 23. In de novo synthesis, serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting …show more content…

Ketosphinganine is reduced to form sphinganine, which is posteriorly N-acylated with fatty acids of different chain lengths by ceramide synthases (CerS), producing dihydroceramides. Six types of CerS exist in mammals, each one encoded by a different gene (CERS1 to CERS6). Because each CerS is specific to different lengths of fatty-acyl CoAs, they determine the acyl chain length of sphingolipids, including ceramides, sphingomyelin and glycosphingolipids. Several studies suggest that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models24,25. Under this new evidence, alterations in the relative balance of molecular species with different acyl-chain lengths might be of pathogenic relevance for complex disorders like ADHD. We found variants in 3 out of the 6 genes encoding for CerS significantly associated with ADHD (CERS6 rs4668077, p-value=0.006; CERS4 rs17160349, p-value=0.039; CERS3 rs1023783, p-value=0.015), with 2 of these variants representing missense mutation encoding for significant changes in the protein amino-acid sequence (rs17160349 and rs1023783). An interesting –although non-significant- trend was also observed for a

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