小柯机器人

线粒体中α-突触核蛋白(α-Syn)的病理结构转换会诱导神经元毒性，这一成果由英国伦敦大学学院Sonia Gandhi、Andrey Y. Abramov和爱丁堡大学Mathew H. Horrocks研究团队合作取得。这一研究成果发表在2022年8月30日出版的国际学术期刊《自然-神经科学》上。

在本研究中，研究人员使用单分子Förster共振能量转移(smFRET)生物传感器跟踪了α-Syn的细胞内构象状态，研究展示了α-Syn在神经元中从单体状态转变为两种不同寡聚状态的过程，分别以浓度依赖性和序列特异性方式发生。三维FRET相关光学和电子显微镜 (FRET-CLEM)显示细胞内起始事件优先发生在膜表面，尤其是在线粒体膜上。线粒体脂质心磷脂引发A53T α-Syn的快速寡聚化，心磷脂被封闭在脂质-蛋白质聚集的复合物中。

线粒体聚集体会损害复合物I的活性并增加线粒体内活性氧(ROS)的生成，从而加速A53T α-Syn的寡聚化并导致线粒体膜透化和细胞死亡。在携带A53T突变帕金森病(PD)患者的诱导多能干细胞(iPSC)衍生神经元中也观察到了这些过程。该研究揭示了线粒体膜α-Syn从头寡聚化和随后产生神经元毒性的机制。

据了解，尽管尚未在神经元内部直接观察到自组装和结构转换的初始阶段，但α-突触核蛋白的聚集会导致帕金森病。

附：英文原文

Title: Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Author: Choi, Minee L., Chappard, Alexandre, Singh, Bhanu P., Maclachlan, Catherine, Rodrigues, Margarida, Fedotova, Evgeniya I., Berezhnov, Alexey V., De, Suman, Peddie, Christopher J., Athauda, Dilan, Virdi, Gurvir S., Zhang, Weijia, Evans, James R., Wernick, Anna I., Zanjani, Zeinab Shadman, Angelova, Plamena R., Esteras, Noemi, Vinokurov, Andrey Y., Morris, Katie, Jeacock, Kiani, Tosatto, Laura, Little, Daniel, Gissen, Paul, Clarke, David J., Kunath, Tilo, Collinson, Lucy, Klenerman, David, Abramov, Andrey Y., Horrocks, Mathew H., Gandhi, Sonia

Issue&Volume: 2022-08-30

Abstract: Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Frster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.

DOI: 10.1038/s41593-022-01140-3

Source: https://www.nature.com/articles/s41593-022-01140-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex