Nature Neurosci—帕金森病研究重磅突破：线粒体α-synuclein的病理性结构转变诱导神经毒性

中文摘要

尽管在神经元内部科学家尚未直接观察到α-Syn自组装和结构转换的初始阶段证据，但α-突触核蛋白（α-Syn）的异常聚集一直被认为驱动了帕金森病（PD）的发生。在这项研究中，研究人员使用单分子Förster共振能量转移（smFRET）生物传感器示踪了α-Syn的细胞内构象状态。他，他们的研究显示，α-Syn以浓度依赖性和序列特异性的方式在神经元中从单体状态转变为两种不同的寡聚体状态。三维FRET相关光和电子显微镜（FRET-CLEM）显示细胞内“播散”事件优先发生在膜表面，尤其是线粒体膜。线粒体脂质心磷脂触发A53Tα-Syn的快速寡聚化，心磷脂被隔离在聚集的脂质蛋白复合物中。线粒体的异常聚集体可损害复合物I的活性并增加线粒体活性氧（ROS）的生成，这加速了A53Tα-Syn的寡聚化并导致线粒体膜的通透性增加和细胞死亡。这些过程也在PD患者诱导的多功能干细胞（iPSC）衍生的含有A53T突变的神经元中观察到。他们的研究揭示了线粒体膜上α-Syn从头寡聚化和诱导神经元毒性的分子机制。

英文摘要

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 Förster 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.

参考文献：Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nat Neurosci. 2022 Sep;25(9):1134-1148.

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