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  2. Exogenous L-fucose attenuates depression induced by chronic unpredictable stress: implicating core fucosylation has an antidepressant potential

Exogenous L-fucose attenuates depression induced by chronic unpredictable stress: implicating core fucosylation has an antidepressant potential

  • J Biol Chem. 2025 Jan 24:108230. doi: 10.1016/j.jbc.2025.108230.
Dan Wang 1 Tomohiko Fukuda 2 Tiangui Wu 1 Xing Xu 1 Tomoya Isaji 3 Jianguo Gu 4
Affiliations

Affiliations

  • 1 Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University.
  • 2 Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. Electronic address: tfukuda@tohoku-mpu.ac.jp.
  • 3 Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
  • 4 Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. Electronic address: jgu@tohoku-mpu.ac.jp.
Abstract

Core fucosylation is one of the most essential modifications of the N-glycans, catalyzed by α1,6-fucosyltransferase (Fut8), which transfers fucose from guanosine 5'-diphosphate (GDP)-fucose to the innermost N-acetylglucosamine residue of N-glycans in an α1-6 linkage. Our previous studies demonstrated that lipopolysaccharide (LPS) can induce a more robust neuroinflammatory response in Fut8 homozygous knockout (KO) (Fut8-/-) and heterozygous KO (Fut8+/-) mice contrasted to the wild-type (Fut8+/+) mice. Exogenous administration of L-fucose suppressed LPS-induced neuroinflammation. Numerous studies indicate that neuroinflammation plays a vital role in the development of depression. Here, we investigated whether core fucosylation regulates depression induced by chronic unpredictable stress (CUS), a well-established model for depression. Our results showed that Fut8+/- mice exhibited depressive-like behaviors and increased neuroinflammation earlier than Fut8+/+ mice. Administration of L-fucose significantly reduced CUS-induced depressive-like behaviors and pro-inflammatory cytokine levels in Fut8+/- mice. The L-fucose treatment produced antidepressant effects by attenuating the complex formation between gp130 and the interleukin-6 (IL-6) receptor and the JAK2/STAT3 signaling pathway. Notably, L-fucose treatment increased dendritic spine density and postsynaptic density protein 95 (PSD-95) expression, which were suppressed in CUS-induced depression. Furthermore, the effects of L-fucose on the CUS-induced depression were also observed in Fut8+/+ mice. Our results clearly demonstrate that L-fucose ameliorates neuroinflammation and synaptic defects in CUS-induced depression, implicating that core fucosylation has significant anti-neuroinflammatory activity and an antidepressant potential.

Keywords

Core fucosylation; Fut8; L-fucose; depression; neuroinflammation.

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