Very-long-chain fatty acids are crucial to neuronal polarity by providing sphingolipids to lipid rafts

Fatty acids (FAs) are important for brain development, and have been shown to play an important role in neuronal differentiation and neurogenesis.  However, the precise functions and types of FAs that are important for neuronal differentiation are still under intense investigation.  Recently, Honda et al. identified a role for very-long-chain fatty acids (VLCFAs) in the regulation of neuronal polarity.  Previous proteomics studies by the group identified that the GPSN2 (2,3-trans-enoyl CoA reductase) protein, which functions to synthesize VLFCAs, was highly enriched in neuronal growth cones.  Thus, the group created GPSN2 knockout mice to further elucidate its role in neuronal growth development.  While homozygous knockout was embryonic lethal, neurons from the heterozygous GPSN2 mice showed definitive, impaired neuronal development.  The group utilized cultured neuronal models from these heterozygous mice, to confirm that depletion of GPSN2 resulted in shorter axons, which could be rescued by GPSN2 overexpression.  The data suggested that GPSN2 regulated neuronal polarity, and the group sought to determine VLCFAs precise role in this function.  Lipidomic studies were performed, and it was determined that sphingolipids had reduced ceramide-C24 FAs in GPSN-depleted or knockout models.  This led to further examination of lipid rafts, which was accomplished by comparing lipid-raft markers to the general membrane profile.  The results showed that WT neuronal growth cones had high concentrations of lipid rafts, while GPSN2 heterozygous neuronal growth cones were devoid of lipid rafts.  To confirm the importance of VLCAs, the group added back ceramide with VLCAs and this was sufficient to rescue lipid raft formation, proper growth cone morphology, and neuronal polarity.  Cytoskeleton Inc’s MemGlow 590 membrane probe (Cat. # MG03) was essential for the effective labeling of neuronal cells for lipid raft analysis. 


Figure Legend: The Schematic shows how GPSN2, which regulates very-long-chain fatty acid synthesis affects neuronal polarity.