Docosahexaenoic Acid Promotes Axon Outgrowth by Translational Regulation of Tau and Collapsin Response Mediator Protein 2 Expression

• Published in: The Journal of biological chemistry Vol. 291; no. 10; pp. 4955 - 4965
• Main Authors: Mita, Toshinari, Mayanagi, Taira, Ichijo, Hiroshi, Fukumoto, Kentaro, Otsuka, Kotaro, Sakai, Akio, Sobue, Kenji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Axons - drug effects; Axons - metabolism; Cells, Cultured; Docosahexaenoic Acids - pharmacology; Intercellular Signaling Peptides and Proteins; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; neurite outgrowth; Neurobiology; neurodevelopment; Neurogenesis; neuron; Proto-Oncogene Proteins c-akt - metabolism; PUFA; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases - metabolism; S6 kinase; Second Messenger Systems; tau Proteins - genetics; tau Proteins - metabolism; TOR Serine-Threonine Kinases - metabolism; translation control; neuron; S6 kinase; neurite outgrowth; translation control; neurodevelopment; PUFA
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.693499

n-3 PUFAs are essential for neuronal development and brain function. However, the molecular mechanisms underlying their biological effects remain unclear. Here we examined the mechanistic action of docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acids in the brain. We found that DHA treatment of cortical neurons resulted in enhanced axon outgrowth that was due to increased axon elongation rates. DHA-mediated axon outgrowth was accompanied by the translational up-regulation of Tau and collapsin response mediator protein 2 (CRMP2), two important axon-related proteins, and the activation of Akt and p70 S6 kinase. Consistent with these findings, rapamycin, a potent inhibitor of mammalian target of rapamycin (mTOR), prevented DHA-mediated axon outgrowth and up-regulation of Tau and CRMP2. In addition, DHA-dependent activation of the Akt-mTOR-S6K pathway enhanced 5′-terminal oligopyrimidine tract-dependent translation of Tau and CRMP2. Therefore, our results revealed an important role for the Akt-mTOR-S6K pathway in DHA-mediated neuronal development.