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Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-04-27 , DOI: 10.1038/s41418-020-0542-z
Plamena R Angelova 1 , Minee L Choi 1, 2 , Alexey V Berezhnov 3, 4 , Mathew H Horrocks 5, 6 , Craig D Hughes 6 , Suman De 6, 7 , Margarida Rodrigues 6, 7 , Ratsuda Yapom 8 , Daniel Little 9, 10 , Karamjit S Dolt 8 , Tilo Kunath 8 , Michael J Devine 9 , Paul Gissen 9, 10 , Mikhail S Shchepinov 11 , Sergiy Sylantyev 1, 12 , Evgeny V Pavlov 13 , David Klenerman 6, 7 , Andrey Y Abramov 1, 4 , Sonia Gandhi 1, 2
Affiliation  

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 α-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 α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-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 β-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.

中文翻译:

α突触核蛋白聚集驱动铁死亡:铁、钙和脂质过氧化作用的相互作用。

蛋白质聚集和异常脂质稳态都通过未知机制参与神经变性。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-膜相互作用取决于聚集体的构象结构,以及脂质膜的氧化态。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细胞膜结合的 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-突触核蛋白寡聚体掺入膜中,生理浓度的谷氨酸和多巴胺会诱导异常钙信号传导,导致膜电导改变和钙内流异常。α-突触核蛋白寡聚体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。脂质过氧化的抑制和自由基铁依赖性积累的减少进一步防止了低聚物诱导的人类神经元毒性。总之,我们报告说,多不饱和脂肪酸的过氧化作用是将富含 β-折叠的聚集体掺入细胞膜的基础,并且还会诱导神经元死亡。这表明铁死亡在帕金森病中的作用,并突出了脂质过氧化导致细胞死亡的新机制。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。脂质过氧化的抑制和自由基铁依赖性积累的减少进一步防止了低聚物诱导的人类神经元毒性。总之,我们报告说,多不饱和脂肪酸的过氧化作用是将富含 β-折叠的聚集体掺入细胞膜的基础,并且还会诱导神经元死亡。这表明铁死亡在帕金森病中的作用,并突出了脂质过氧化导致细胞死亡的新机制。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。脂质过氧化的抑制和自由基铁依赖性积累的减少进一步防止了低聚物诱导的人类神经元毒性。总之,我们报告说,多不饱和脂肪酸的过氧化作用是将富含 β-折叠的聚集体掺入细胞膜的基础,并且还会诱导神经元死亡。这表明铁死亡在帕金森病中的作用,并突出了脂质过氧化导致细胞死亡的新机制。和减少自由基的铁依赖性积累,进一步防止低聚物诱导的人类神经元毒性。总之,我们报告说,多不饱和脂肪酸的过氧化作用是将富含 β-折叠的聚集体掺入细胞膜的基础,并且还会诱导神经元死亡。这表明铁死亡在帕金森病中的作用,并突出了脂质过氧化导致细胞死亡的新机制。和减少自由基的铁依赖性积累,进一步防止低聚物诱导的人类神经元毒性。总之,我们报告说,多不饱和脂肪酸的过氧化作用是将富含 β-折叠的聚集体掺入细胞膜的基础,并且还会诱导神经元死亡。这表明铁死亡在帕金森病中的作用,并突出了脂质过氧化导致细胞死亡的新机制。
更新日期:2020-04-27
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