| Summary: | α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D<sub>2L</sub>). Here, we investigated the importance of dopamine D<sub>2L</sub> receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D<sub>2L</sub><sup>−/−</sup>, dopamine D2 receptor null (D2 null), FABP3<sup>−/−</sup>, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D<sub>2L</sub> receptors are co-localized with FABP3. Immunocytochemistry revealed that TH<sup>+</sup> D2L<sup>−/−</sup> or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D<sub>2L</sub> and FABP3 were also critical for α-synuclein fibrils uptake. D<sub>2L</sub> and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D<sub>2L</sub> with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease.
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