Program

OR5-4

Discovery of disease-modifying drug inhibiting alpha-synuclein aggregation in Parkinson's disease model mice

[Speaker] Kohji Fukunaga:1
[Co-author] Yasushi Yabuki:1, Kazuya Matsuo:1, Hisanao Izumi:1, Yasuharu Shinoda:1
1:Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences, Japan

[Backgrounds] Accumulation and aggregation of alpha-synuclein in dopaminergic neurons is one of pathogenesis of Parkinson's disease (PD) and its aggregation is partly regulated by long-chain polyunsaturated fatty acids (LCPUFAs) such as arachidonic acid (AA). Fatty acid binding protein 3 (FABP3, H-FABP) is critical for AA transport and metabolism in the brain. We recently demonstrated that FABP3 is highly expressed in dopaminergic neurons, especially in the substantia nigra pars compacta (SNpc) (Shioda and Fukunaga et al., J Biol Chem 2014;289:18957). We here addressed the pathophysiological relevance of FABP3 using PD model mice. We also defined potent neuroprotective action of FABP3 ligands in PD model mice.
[Methods] Wild and FABP3 KO mice were treated with 1-methyl-1,2,3,6-tetrahydropiridine (MPTP) and investigated its neurotoxicity in the SNpc. Mice were treated for 2-3 weeks by orally FABP3 ligands, novel candidates of PD therapeutics.
[Results] FABP3 KO mice were resistant to MPTP-induced dopaminergic neurodegeneration and motor deficits. Importantly, MPTP-induced alpha-synuclein accumulation in SNpc was attenuated in FABP3 KO mice as compared with that in wild-type mice. DA neurons in SNpc were largely degenerated by MPTP treatment concomitant with alpha-synuclein accumulation in neural cell bodies. On the other hand, FABP3 ligands totally inhibited both alpha-synuclein accumulation and cell death. Finally, novel FABP3 ligands ameliorated MPTP-induced both motor and cognitive functions observed in MPTP-treated mice.
[Conclusion] Taken together, the formation of oligomers of alpha-synuclein is promoted by FABP3 through AA binding to FABP3 in dopaminergic neurons, thereby causing neuronal death seen in PD. We here introduce disease-modifying therapeutics, FABP ligands to prevent synucleinopathies in PD. This research is supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED (http://lewybody2016.jp/). The authors declare no conflict of interests.

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