Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP(+)-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons

α-Synuclein is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson′s disease and other synucleinopathies. Fatty acids partially regulate α-Synuclein accumulation, and mesencephalic dopaminergic neurons highly express fatty acid-binding protein 3 (FABP3). We previously demonstrated that FABP3 knockout mice show decreased α-Synuclein oligomerization and neuronal degeneration of tyrosine hydroxylase (TH)-positive neurons in vivo. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP(+))-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3(−/−) C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH(+) neurons from FABP3(+/+) mice take up α-Synuclein monomers while FABP3(−/−) TH(+) neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP(+) was observed only in FABP3(+/+), and not in FABP3(−/−) neurons. Notably, detailed morphological analysis revealed that FABP(−/−) neurons did not exhibit MPP(+)-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP(+)-induced reduction of mitochondrial activity and the production of reactive oxygen species. These data indicate that FABP3 is critical for α-Synuclein uptake in dopaminergic neurons, thereby preventing synucleinopathies, including Parkinson′s disease.