α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.
α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.
复制标题
DOI：
10.1038/s41467-018-04422-2
复制
发表时间：
2018-06-12
影响因子：
16.6
通讯作者：
Gandhi S
中科院分区：
文献类型：
--
作者：
Ludtmann MHR;Angelova PR;Horrocks MH;Choi ML;Rodrigues M;Baev AY;Berezhnov AV;Yao Z;Little D;Banushi B;Al-Menhali AS;Ranasinghe RT;Whiten DR;Yapom R;Dolt KS;Devine MJ;Gissen P;Kunath T;Jaganjac M;Pavlov EV;Klenerman D;Abramov AY;Gandhi S
蛋白质聚集导致α-突触核蛋白从其生理作用转变为病理性毒性功能获得。在生理条件下，单体α-突触核蛋白提高ATP合成酶的效率。在这里，我们报告说，单体的聚集产生富含β-片层的寡聚体，这些寡聚体定位于线粒体中，与包括ATP合酶在内的几种线粒体蛋白非常接近。寡聚体α-突触核蛋白损害复合物I依赖性呼吸。寡聚体诱导ATP合酶β亚基的选择性氧化和线粒体脂质过氧化。这些氧化事件增加了渗透性转换孔（PTP）打开的可能性，触发线粒体肿胀，并最终导致细胞死亡。值得注意的是，寡聚体诱导的氧化的抑制防止PTP的病理诱导。携带SNCA三倍的诱导性多能干细胞（iPSC）衍生的神经元产生α-突触核蛋白聚集体，其与ATP合酶相互作用并诱导PTP开放，导致神经元死亡。这项研究显示了α-突触核蛋白从单体结构到寡聚体结构的转变如何改变其在帕金森病中的功能后果。α-突触核蛋白的毒性聚集形式如何导致神经变性尚不清楚。在这里，作者使用生物物理学和细胞成像方法来显示α-突触核蛋白的特定寡聚体对线粒体产生影响，诱导渗透性转换孔的开放，导致帕金森病中的细胞死亡。
Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson’s disease. How toxic aggregated forms of α-synuclein lead to neurodegeneration is unclear. Here authors use biophysical and cellular imaging methods to show that specific oligomers of α-synuclein exert effects on mitochondria to induce opening of the permeability transition pore, leading to cell death in Parkinson’s disease.
登录
查看更多内容
线粒体通透性过渡孔是线粒体钙外排的可分配元件。
影响因子：
4
作者：
De Marchi E;Bonora M;Giorgi C;Pinton P
通讯作者：
Pinton P
影响因子：
4
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
通讯作者：
Abramov AY
影响因子：
3.7
作者：
Flierl A;Oliveira LM;Falomir-Lockhart LJ;Mak SK;Hesley J;Soldner F;Arndt-Jovin DJ;Jaenisch R;Langston JW;Jovin TM;Schüle B
通讯作者：
Schüle B
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
3.9
作者：
Allsop, David;Mayes, Jennifer;Tabner, Brian J.
通讯作者：
Tabner, Brian J.