Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons.
Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons.
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DOI：
10.3390/biomedicines9010049
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发表时间：
2021-01-08
期刊：
影响因子：
4.7
通讯作者：
Fukunaga K
中科院分区：
文献类型：
--
作者：
Kawahata I;Sekimori T;Wang H;Wang Y;Sasaoka T;Bousset L;Melki R;Mizobata T;Kawata Y;Fukunaga K
α-突触核蛋白在多巴胺能神经元中的积聚是帕金森病的一个病理特征。我们先前已经证明，脂肪酸结合蛋白3(FABP3)对于α-突触核蛋白的摄取和繁殖在多巴胺能神经元中积累是至关重要的。FABP3在多巴胺能神经元中含量丰富，并与多巴胺D2受体相互作用，特别是长型(D2L)。在这里，我们研究了多巴胺D2L受体在摄取α-突触核蛋白单体及其纤维中的重要性。我们使用了来自多巴胺D2L−/−、多巴胺D2受体缺失(D2 Null)、FABP3−/−和野生型C57BL6小鼠的中脑神经元，并分析了荧光标记的α-突触核蛋白单体和纤维的摄取能力。我们发现D2L受体与FABP3是共定位的。免疫细胞化学显示TH+D2L−/−或D2缺失神经元不摄取α-突触核蛋白单体。α突触核蛋白C末端的缺失完全取消了对多巴胺神经元的摄取。同样，动力蛋白抑制剂王朝和小窝蛋白-1基因敲除也取消了这种摄取。D2L和FABP3也是α突触核蛋白纤维摄取的关键。D2L和累积的α-突触核蛋白纤维很好地共定位。这些数据表明，具有凹陷结构的多巴胺D2L与FABP3偶联是多巴胺能神经元摄取α-突触核蛋白的关键，这可能是包括帕金森病在内的突触核病的一种新的致病机制。
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 (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L−/−, dopamine D2 receptor null (D2 null), FABP3−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D2L−/− 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. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L 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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