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

An Cheng, Yasuharu Shinoda, Tetsunori Yamamoto, Hiroyuki Miyachi, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)190-197
Number of pages8
JournalBrain research
Volume1707
DOIs
Publication statusPublished - 2019 Mar 15

Keywords

  • Arachidonic acid
  • FABP ligands
  • FABP3
  • Parkinson's disease
  • αSyn oligomerization

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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