| 1 | J. Biol. Chem. 2011 May 286: 18434-43 |
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| PMID | 21471224 |
| Title | Alpha1,6-fucosyltransferase-deficient mice exhibit multiple behavioral abnormalities associated with a schizophrenia-like phenotype: importance of the balance between the dopamine and serotonin systems. |
| Abstract | Previously, we reported that ?1,6-fucosyltransferase (FUT8)-deficient (FUT8(-/-)) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-?1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of ?1,6-fucosylation in brain tissue where FUT8 is highly expressed, we examined FUT8(-/-) mice using a combination of neurological and behavioral tests. FUT8(-/-) mice exhibited multiple behavioral abnormalities consistent with a schizophrenia-like phenotype. FUT8(-/-) mice displayed increased locomotion compared with wild-type (FUT8(+/+)) and heterozygous (FUT8(+/-)) mice. In particular, FUT8(-/-) mice showed strenuous hopping behavior in a novel environment. Working memory performance was impaired in FUT8(-/-) mice as evidenced by the Y-maze tests. Furthermore, FUT8(-/-) mice showed prepulse inhibition (PPI) deficiency. Intriguingly, although there was no significant difference between FUT8(+/+) and FUT8(+/-) mice in the PPI test under normal conditions, FUT8(+/-) mice showed impaired PPI after exposure to a restraint stress. This result suggests that reduced expression of FUT8 is a plausible cause of schizophrenia and related disorders. The levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the FUT8(-/-) mice. Likewise, treatment with haloperidol, which is an antipsychotic drug that antagonizes dopaminergic and serotonergic receptors, significantly reduced hopping behaviors. The present study is the first to clearly demonstrate that ?1,6-fucosylation plays an important role in the brain, and that it might be related to schizophrenia-like behaviors. Thus, the results of the present study provide new insights into the underlying mechanisms responsible for schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia |
| 2 | FASEB J. 2013 Oct 27: 3947-58 |
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| PMID | 23796784 |
| Title | ?1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-?/activin-mediated signaling. |
| Abstract | It is well known that ?1,6-fucosyltransferase (FUT8) and its products, ?1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that FUT8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that ?1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of ?1,6-fucosylation. The knockdown (KD) of FUT8 promoted a significant enhancement of neurite formation and induction of neurofilament expression. Surprisingly, the levels of phospho-Smad2 were greatly increased in the KD cells. Finally, we found that the activin-mediated signal pathway was essential for these changes in KD cells. Exogenous activin, not TGF-?1, induced neurite outgrowth and phospho-Smad2. In addition, the ?1,6-fucosylation level on the activin receptors was greatly decreased in KD cells, while the total expression level was unchanged, suggesting that ?1,6-fucosylation negatively regulated activin-mediated signaling. Furthermore, inhibition of activin receptor-mediated signaling or restoration of FUT8 expression rescued cell morphology and phospho-Smad2 levels, which were enhanced in KD cells. Considering the fact that ?1,6-fucosylation is important for TGF-?-mediated signaling, the results of this study strongly suggest that FUT8 plays a dual role in TGF-?/activin-mediated signaling. |
| SCZ Keywords | schizophrenia |
| 3 | J. Biol. Chem. 2015 Jul 290: 17566-75 |
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| PMID | 25979332 |
| Title | Loss of ?1,6-Fucosyltransferase Decreases Hippocampal Long Term Potentiation: IMPLICATIONS FOR CORE FUCOSYLATION IN THE REGULATION OF AMPA RECEPTOR HETEROMERIZATION AND CELLULAR SIGNALING. |
| Abstract | Core fucosylation is catalyzed by ?1,6-fucosyltransferase (FUT8), which transfers a fucose residue to the innermost GlcNAc residue via ?1,6-linkage on N-glycans in mammals. We previously reported that FUT8-knock-out (FUT8(-/-)) mice showed a schizophrenia-like phenotype and a decrease in working memory. To understand the underlying molecular mechanism, we analyzed early form long term potentiation (E-LTP), which is closely related to learning and memory in the hippocampus. The scale of E-LTP induced by high frequency stimulation was significantly decreased in FUT8(-/-) mice. Tetraethylammonium-induced LTP showed no significant differences, suggesting that the decline in E-LTP was caused by postsynaptic events. Unexpectedly, the phosphorylation levels of calcium/calmodulin-dependent protein kinase II (CaMKII), an important mediator of learning and memory in postsynapses, were greatly increased in FUT8(-/-) mice. The expression levels of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the postsynaptic density were enhanced in FUT8(-/-) mice, although there were no significant differences in the total expression levels, implicating that AMPARs without core fucosylation might exist in an active state. The activation of AMPARs was further confirmed by Fura-2 calcium imaging using primary cultured neurons. Taken together, loss of core fucosylation on AMPARs enhanced their heteromerization, which increase sensitivity for postsynaptic depolarization and persistently activate N-methyl-d-aspartate receptors as well as Ca(2+) influx and CaMKII and then impair LTP. |
| SCZ Keywords | schizophrenia |