Dopamine D2 long receptors are critical for caveolae-mediated $\alpha$-synuclein uptake in cultured dopaminergic neurons - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue Biomedicines Année : 2021

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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cea-03116063 , version 1 (20-01-2021)

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Ichiro Kawahata, Tomoki Sekimori, Haoyang Wang, Yanyan Wang, Toshikuni Sasaoka, et al.. Dopamine D2 long receptors are critical for caveolae-mediated $\alpha$-synuclein uptake in cultured dopaminergic neurons. Biomedicines, 2021, 9, pp.49. ⟨10.3390/biomedicines9010049⟩. ⟨cea-03116063⟩
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