Dopamine D2 long receptors are critical for caveolae-mediated $\alpha$-synuclein uptake in cultured dopaminergic neurons
Résumé
a-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
a-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$_{2L}$).
Here, we investigated the importance of dopamine D$_{2L}$ receptors in the uptake of a-synuclein
monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D$_{2L}$
-/-, dopamine D2 receptor null (D2 null), FABP3-/-, and wild type C57BL6 mice, and analyzed the
uptake ability of fluorescence-conjugated a-synuclein monomers and fibrils. We found that D$_{2L}$
receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D$_{2L}$/- or D2 null
neurons do not take up a-synuclein monomers. The deletion of a-synuclein C-terminus completely
abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1
knockdown also abolished the uptake. D$_{2L}$ and FABP3 were also critical for a-synuclein fibrils
uptake. D$_{2L}$ and accumulated a-synuclein fibrils were well co-localized. These data indicate that
dopamine D$_{2L}$ with a caveola structure coupled with FABP3 is critical for a-synuclein uptake by
dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including
Parkinson’s disease.
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