Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation
Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation
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DOI：
10.1038/s41418-020-0542-z
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发表时间：
2020-04-27
影响因子：
12.4
通讯作者：
Gandhi, Sonia
中科院分区：
文献类型：
--
作者：
Angelova, Plamena R.;Choil, Minee L.;Gandhi, Sonia
蛋白质聚集和脂质稳态异常都通过未知机制参与神经退行性变。在这里，我们证明聚集体-膜相互作用对于诱导一种称为铁死亡的细胞死亡形式至关重要。重要的是，驱动铁死亡的聚集体-膜相互作用既取决于聚集体的构象结构，也取决于脂质膜的氧化态。我们生成了人类干细胞衍生的突触核蛋白病模型，其特征是细胞内形成与膜结合的α-突触核蛋白聚集体。在具有 SNCA 三倍体的人 iPSC 衍生神经元中，由于过量的 α-突触核蛋白寡聚物掺入膜中，生理浓度的谷氨酸和多巴胺会诱导异常的钙信号传导，导致膜电导改变和异常的钙内流。 α-突触核蛋白寡聚物进一步诱导脂质过氧化。脂质过氧化的靶向抑制可防止聚集体-膜相互作用，消除异常的钙通量，并恢复生理钙信号传导。抑制脂质过氧化并减少铁依赖性自由基积累，进一步防止低聚物诱导的人类神经元毒性。总之，我们报告多不饱和脂肪酸的过氧化是富含β折叠的聚集体掺入细胞膜的基础，并且这还诱导神经元死亡。这表明铁死亡在帕金森病中的作用，并强调了脂质过氧化导致细胞死亡的新机制。
Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of alpha-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess alpha-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. alpha-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of beta-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson's disease, and highlights a new mechanism by which lipid peroxidation causes cell death.