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

Atsuko Honda; Motohiro Nozumi; Yasuyuki Ito; Rie Natsume; Asami Kawasaki; Fubito Nakatsu; Manabu Abe; Haruki Uchino; Natsuki Matsushita; Kazutaka Ikeda; Makoto Arita; Kenji Sakimura; Michihiro Igarashi

doi:10.1016/j.celrep.2023.113195

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

Cell Rep. 2023 Oct 31;42(10):113195. doi: 10.1016/j.celrep.2023.113195. Epub 2023 Oct 9.

Authors

Affiliations

¹ Department of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan; Center for Research Promotion, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
² Department of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
³ Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Chuo-ku, Niigata 951-8585, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Chuo-ku, Niigata 951-8585, Japan.
⁴ Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama 230-0045, Japan; Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo 105-8512, Japan.
⁵ Division of Laboratory Animal Research, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
⁶ Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
⁷ Department of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan. Electronic address: tarokaja@med.niigata-u.ac.jp.

PMID: 37816355
DOI: 10.1016/j.celrep.2023.113195

Abstract

Fatty acids have long been considered essential to brain development; however, the involvement of their synthesis in nervous system formation is unclear. We generate mice with knockout of GPSN2, an enzyme for synthesis of very-long-chain fatty acids (VLCFAs) and investigate the effects. Both GPSN2^-/- and GPSN2^+/- mice show abnormal neuronal networks as a result of impaired neuronal polarity determination. Lipidomics of GPSN2^-/- embryos reveal that ceramide synthesis is specifically inhibited depending on FA length; namely, VLCFA-containing ceramide is reduced. We demonstrate that lipid rafts are highly enriched in growth cones and that GPSN2^+/- neurons lose gangliosides in their membranes. Application of C24:0 ceramide, but not C16:0 ceramide or C24:0 phosphatidylcholine, to GPSN2^+/- neurons rescues both neuronal polarity determination and lipid-raft density in the growth cone. Taken together, our results indicate that VLCFA synthesis contributes to physiological neuronal development in brain network formation, in particular neuronal polarity determination through the formation of lipid rafts.

Keywords: CP: Cell biology; CP: Neuroscience.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ceramides*
Fatty Acids
Membrane Microdomains
Mice
Neurons
Sphingolipids*

Substances

Sphingolipids
Ceramides
Fatty Acids