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Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress

Abstract

We previously show that fatty acid-binding protein 3 (FABP3) triggers α-synuclein (Syn) accumulation and induces dopamine neuronal cell death in Parkinson disease mouse model. But the role of fatty acid-binding protein 7 (FABP7) in the brain remains unclear. In this study we investigated whether FABP7 was involved in synucleinopathies. We showed that FABP7 was co-localized and formed a complex with Syn in Syn-transfected U251 human glioblastoma cells, and treatment with arachidonic acid (100 M) significantly promoted FABP7-induced Syn aggregation, which was associated with cell death. We demonstrated that synthetic FABP7 ligand 6 displayed a high affinity against FABP7 with Kd value of 209 nM assessed in 8-anilinonaphthalene-1-sulfonic acid (ANS) assay; ligand 6 improved U251 cell survival via disrupting the FABP7–Syn interaction. We showed that activation of phospholipase A2 (PLA2) by psychosine (10 M) triggered oligomerization of endogenous Syn and FABP7, and induced cell death in both KG-1C human oligodendroglia cells and oligodendrocyte precursor cells (OPCs). FABP7 ligand 6 (1 M) significantly decreased Syn oligomerization and aggregation thereby prevented KG-1C and OPC cell death. This study demonstrates that FABP7 triggers α-synuclein oligomerization through oxidative stress, while FABP7 ligand 6 can inhibit FABP7-induced Syn oligomerization and aggregation, thereby rescuing glial cells and oligodendrocytes from cell death.

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Fig. 1: FABP7 forms a complex and colocalizes with αSyn and AA induces αSyn oligomerization in αSyn-transfected U251 cells.
Fig. 2: In vitro evaluation of FABP7 ligands in disrupting αSyn/FABP7 interaction.
Fig. 3: Synthetic FABP7 ligands reduce αSyn oligomerization and aggregation.
Fig. 4: Synthetic FABP7 ligands improve U251 cell survival.
Fig. 5: Functions of FABP7 in OLGs.
Fig. 6: FABP7 and αSyn interaction in OPCs primary culture.
Fig. 7: Schematic representation of the pathways through which FABP7 triggers αSyn oligomerization associated with oxidative stress and induces oligodendrocyte loss.

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Acknowledgements

We gratefully thank The Uehara Memorial Foundation for financial support. This work was supported in part by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071; awarded to KF).

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AC, investigation and original draft writing; YS, investigation; YFW, investigation; IK, investigation and methodology; TY, methodology and validation; WBJ, methodology and validation; HY, methodology; TM, methodology; YK, methodology and validation; KF, supervision, review/editing, project administration and funding.

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Correspondence to Kohji Fukunaga.

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Cheng, A., Wang, Yf., Shinoda, Y. et al. Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress. Acta Pharmacol Sin 43, 552–562 (2022). https://doi.org/10.1038/s41401-021-00675-8

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  • DOI: https://doi.org/10.1038/s41401-021-00675-8

Keywords

  • synucleinopathies
  • α-synuclein oligomerization
  • fatty acid binding protein 7
  • arachidonic acid
  • psychosine
  • cell death

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