Development of FABP3 ligands that inhibit arachidonic acid-induced α-synuclein oligomerization

• Published in: Brain research 2019-03, Vol.1707, p.190-197
• Main Authors: Cheng, An, Shinoda, Yasuharu, Yamamoto, Tetsunori, Miyachi, Hiroyuki, Fukunaga, Kohji
• Format: Article
• Language: English
• Subjects: Arachidonic acid; FABP ligands; FABP3; Parkinson’s disease; αSyn oligomerization
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2018.11.036

•αSyn oligomerization is facilitated by FABP3 expression and AA treatment.•Highly selective FABP3 ligands can be developed using the ANS assay.•The selective FABP3 ligands inhibit AA-induced αSyn oligomerization. In Parkinson’s disease (PD), α-synuclein (αSyn) accumulation and inclusion triggers dopamine neuronal death and synapse dysfunction in vivo. We previously reported that fatty acid-binding protein 3 (FABP3) is highly expressed in the brain and accelerates αSyn oligomerization when cells are exposed to 1-Methyl-1,2,3,6-tetrahydropiridine (MPTP). Here, we demonstrate that αSyn oligomerization was markedly enhanced by co-overexpressing FABP3 in neuro-2A cells when cells were treated with arachidonic acid (AA). We developed FABP3 ligands, which bind to the fatty acid binding domain of FABP3, using an 8-Anilinonaphthalene-1-sulfonic acid (ANS) assay with a recombinant FABP3 protein. The prototype for the FABP4 ligand, BMS309403, has no affinity for FABP3. We developed more FABP3-specific ligands derived from the chemical structure of BMS309403. Like AA, ligands 1, 7, and 8 had a relatively high affinity for FAPB3 in the ANS assay. Then, we evaluated the inhibition of αSyn oligomerization in neuro-2A cells co-overexpressing FABP3 and αSyn. Importantly, AA treatments markedly enhanced αSyn oligomerization in the co-expressing cells. Ligands 1, 7, and 8 significantly reduced AA-induced αSyn oligomerization in neuro-2A cells. Taken together, our results indicate that FABP3 ligands that target FABP3 may be used as potential therapeutics that inhibit αSyn aggregation in vivo.