TY - JOUR
T1 - Development of FABP3 ligands that inhibit arachidonic acid-induced α-synuclein oligomerization
AU - Cheng, An
AU - Shinoda, Yasuharu
AU - Yamamoto, Tetsunori
AU - Miyachi, Hiroyuki
AU - Fukunaga, Koji
N1 - Funding Information:
This work was supported in part by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED (JP17dm0107071) (to K.F.).
PY - 2019/3/15
Y1 - 2019/3/15
N2 - 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.
AB - 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.
KW - Arachidonic acid
KW - FABP ligands
KW - FABP3
KW - Parkinson's disease
KW - αSyn oligomerization
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UR - http://www.scopus.com/inward/citedby.url?scp=85057801194&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2018.11.036
DO - 10.1016/j.brainres.2018.11.036
M3 - Article
C2 - 30496735
AN - SCOPUS:85057801194
VL - 1707
SP - 190
EP - 197
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0006-8993
ER -