| Summary: | 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 <i>in vivo</i>. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3<sup>−/−</sup> C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH<sup>+</sup> neurons from FABP3<sup>+/+</sup> mice take up α-Synuclein monomers while FABP3<sup>−/−</sup> TH<sup>+</sup> neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP<sup>+</sup> was observed only in FABP3<sup>+/+</sup>, and not in FABP3<sup>−/−</sup> neurons. Notably, detailed morphological analysis revealed that FABP<sup>−/−</sup> neurons did not exhibit MPP<sup>+</sup>-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP<sup>+</sup>-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.
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