期刊
ACTA PHARMACOLOGICA SINICA
卷 43, 期 3, 页码 552-562出版社
NATURE PUBL GROUP
DOI: 10.1038/s41401-021-00675-8
关键词
synucleinopathies; α -synuclein oligomerization; fatty acid binding protein 7; arachidonic acid; psychosine; cell death
资金
- Uehara Memorial Foundation
- Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development [JP17dm0107071, JP18dm0107071, JP19dm0107071, JP20dm0107071]
The study demonstrates that FABP7 triggers alpha-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.
We previously show that fatty acid-binding protein 3 (FABP3) triggers alpha-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 K-d 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 alpha-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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