Ca2+ is a key factor in α-synuclein-induced neurotoxicity.
Ca2+ is a key factor in α-synuclein-induced neurotoxicity.
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DOI：
10.1242/jcs.180737
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发表时间：
2016-05-01
影响因子：
4
通讯作者：
Abramov AY
中科院分区：
文献类型：
--
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
α-突触核蛋白的聚集导致低聚中间体的形成，这些中间体可以与膜相互作用形成孔隙。然而，尚不清楚这是如何导致帕金森病的细胞毒性的。我们使用人工膜上的活体神经元成像和电生理学研究了α-突触核蛋白对原代神经元和星形胶质细胞中Ca 2+信号传导的种属特异性影响。我们证明，α-突触核蛋白诱导基础细胞内Ca 2+的增加，在其未折叠的单体状态，以及在其寡聚体状态。人工膜的电生理学表明，α-突触核蛋白单体诱导不规则的离子电流，而α-突触核蛋白寡聚体诱导罕见的离散通道形成事件。尽管单体α-突触核蛋白能够影响Ca 2+信号传导，但只有寡聚体形式的α-突触核蛋白才能诱导细胞死亡。寡聚体诱导的细胞死亡通过排除细胞外Ca 2+而被消除，这阻止了α-突触核蛋白诱导的Ca 2+失调。本研究的结果证实，α-突触核蛋白与膜相互作用，以结构特异性方式影响Ca 2+信号传导，富含寡聚β-片层的α-突触核蛋白种类最终导致Ca 2+失调和Ca 2+依赖性细胞死亡。总结：单体和寡聚体α-突触核蛋白通过掺入膜诱导神经元和星形胶质细胞中的Ca 2+信号。
Aggregation of α-synuclein leads to the formation of oligomeric intermediates that can interact with membranes to form pores. However, it is unknown how this leads to cell toxicity in Parkinson's disease. We investigated the species-specific effects of α-synuclein on Ca2+ signalling in primary neurons and astrocytes using live neuronal imaging and electrophysiology on artificial membranes. We demonstrate that α-synuclein induces an increase in basal intracellular Ca2+ in its unfolded monomeric state as well as in its oligomeric state. Electrophysiology of artificial membranes demonstrated that α-synuclein monomers induce irregular ionic currents, whereas α-synuclein oligomers induce rare discrete channel formation events. Despite the ability of monomeric α-synuclein to affect Ca2+ signalling, it is only the oligomeric form of α-synuclein that induces cell death. Oligomer-induced cell death was abolished by the exclusion of extracellular Ca2+, which prevented the α-synuclein-induced Ca2+ dysregulation. The findings of this study confirm that α-synuclein interacts with membranes to affect Ca2+ signalling in a structure-specific manner and the oligomeric β-sheet-rich α-synuclein species ultimately leads to Ca2+ dysregulation and Ca2+-dependent cell death. Summary: Monomeric and oligomeric α-synuclein induce Ca2+ signal in neurons and astrocytes by incorporating into the membrane.