Alpha-synuclein aggregation and cell death triggered by energy deprivation and dopamine overload are counteracted by D2/D3 receptor activation
Alpha-synuclein aggregation and cell death triggered by energy deprivation and dopamine overload are counteracted by D2/D3 receptor activation
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DOI：
10.1111/j.1471-4159.2008.05406.x
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Spano, PierFranco
中科院分区：
文献类型：
--
作者：
Bellucci, Arianna;Collo, Ginetta;Spano, PierFranco
黑质纹状体系统多巴胺能细胞中进行性变性和由丝状 α-突触核蛋白 (α-syn) 组成的神经元内路易体是帕金森病 (PD) 的特征。受帕金森病神经退行性变化影响的一些大脑区域的葡萄糖摄取减少。在帕金森病患者的大脑中观察到黑质线粒体活性缺陷，黑质病变可诱发继发性帕金森病的发作。因此，能量饥饿以及随后的多巴胺能神经元代谢损伤可能与帕金森病的发生有关。在这方面，我们评估了在原代中头神经元培养物和多巴胺能分化的 SH-SY5Y 细胞中通过葡萄糖剥夺（GD）“体外”再现的营养饥饿的影响，以评估对多巴胺能细胞的葡萄糖支持减少是否会导致线粒体损伤、神经变性和 α-syn 错误折叠。此外，我们研究了在 DA 摄取抑制剂或 D-2/D-3 受体 (D2R/D3R) 激动剂喹吡罗存在下，多巴胺 (DA) 治疗对 GD 处理的细胞的影响，以评估这些治疗化合物的功效。我们发现，GD 诱导多巴胺能细胞中含有 DA 转运蛋白的纤维聚集 α-syn 内含物的形成。这些改变伴随着多巴胺能细胞死亡，并因多巴胺超载而加剧。相反，阻断 DA 摄取和 D2R/D3R 激动剂治疗可发挥神经保护作用。这些数据表明，葡萄糖饥饿可能参与了多巴胺能神经元 PD 相关病理变化的诱导。这些变化可以通过阻断 DA 摄取和多巴胺能激动剂治疗来抵消。
Progressive degeneration and intraneuronal Lewy bodies made of filamentous alpha-synuclein (alpha-syn) in dopaminergic cells of the nigrostriatal system are characteristics of Parkinson's disease (PD). Glucose uptake is reduced in some of the brain regions affected by PD neurodegenerative changes. Defects in mitochondrial activity in the substantia nigra have been observed in the brain of patients affected by PD and substantia nigra lesions can induce the onset of a secondary parkinsonism. Thus, energy starvation and consequently metabolic impairment to dopaminergic neurons may be related to the onset of PD. On this line, we evaluated the effect of nutrient starvation, reproduced 'in vitro' by glucose deprivation (GD), in primary mesecephalic neuronal cultures and dopaminergic-differentiated SH-SY5Y cells, to evaluate if decreased glucose support to dopaminergic cells can lead to mitochondrial damage, neurodegeneration and alpha-syn misfolding. Furthermore, we investigated the effect of dopamine (DA) treatment in the presence of a DA-uptake inhibitor or of the D-2/D-3 receptor (D2R/D3R) agonist quinpirole on GD-treated cells, to evaluate the efficacy of these therapeutic compounds. We found that GD induced the formation of fibrillary aggregated alpha-syn inclusions containing the DA transporter in dopaminergic cells. These alterations were accompanied by dopaminergic cell death and were exacerbated by DA overload. Conversely, the block of DA uptake and D2R/D3R agonist treatment exerted neuroprotective effects. These data indicate that glucose starvation is likely involved in the induction of PD-related pathological changes in dopaminergic neurons. These changes may be counteracted by the block of DA uptake and by dopaminergic agonist treatment.