Synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca²⁺-induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca²⁺ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca²⁺ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies.

中文翻译：

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RNA G 四链体形成促进神经病理学 α-突触核蛋白聚集的支架


突触核蛋白病，包括帕金森病、路易体痴呆和多系统萎缩，是由 α-突触核蛋白聚集引发的，从而引发进行性神经变性。然而，细胞内 α-突触核蛋白聚集机制仍不清楚。在此，我们证明 RNA G -四链体组装形成 α-突触核蛋白聚集的支架，有助于神经退化。纯化的 α-突触核蛋白直接通过 N 末端结合 RNA G -四链体。RNA G-四链体经历 Ca²⁺ 诱导的相分离和组装，加速 α-突触核蛋白溶胶-凝胶相变。在 α-突触核蛋白预先形成的原纤维处理的神经元中，包含突触 mRNA 的 RNA G -四链体组装在细胞质 Ca²⁺ 过量流入时与 α-突触核蛋白共聚集，引发突触功能障碍。使用光遗传学方法的强制 RNA G 四链体组装会诱发 α-突触核蛋白聚集，导致神经元功能障碍和神经退化。5-氨基乙酰丙酸（一种原卟啉 IX 前药）的给药可防止 RNA G -四链体相分离，从而减弱 α-突触核蛋白预形成的突触核蛋白注射突触核蛋白小鼠的 α-突触核蛋白聚集、神经退行性和进行性运动缺陷。因此，Ca²⁺ 内流诱导的 RNA G-四链体组装加速了 α-突触核蛋白的相变和聚集，可能导致突触核蛋白病。