RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation

Affiliations

• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Center for Biosystems Dynamics Research (BDR), RIKEN, Kobe 50-0047, Japan.
• Department of Pathology and Laboratory Medicine, National Hospital Organization Sendai Medical Center, Sendai 983-8520, Japan.
• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan.
• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.
• Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan.
• Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan.
• Department of Neurology, National Hospital Organization Sendai Nishitaga Hospital, Sendai 982-8555, Japan.
• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: shioda@kumamoto-u.ac.jp.
• Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: yabukiy@kumamoto-u.ac.jp.

PMID:  39426376  DOI: 10.1016/j.cell.2024.09.037

Abstract

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.

包括帕金森病、路易体痴呆症和多系统萎缩在内的突触核蛋白病是由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-突触核蛋白的聚集机制仍不清楚。在此，我们证明了 RNA G-四联体组装形成了α-突触核蛋白聚集的支架，从而导致神经退行性变。纯化的α-突触核蛋白通过N末端直接与RNA G-四联体结合。RNA G-四联体在 Ca2+ 诱导下发生相分离和组装，加速了α-突触核蛋白的溶胶-凝胶相转变。在经过α-突触核蛋白预成纤维处理的神经元中，突触mRNA组成的RNA G-四联体在过量的细胞质Ca2+流入时与α-突触核蛋白共同聚集，导致突触功能障碍。利用光遗传学方法强迫 RNA G-四联体组装会诱发α-突触核蛋白聚集，导致神经元功能障碍和神经退行性变。服用原卟啉 IX 原药 5-aminolevulinic acid 可以防止 RNA G-quadruplex 相分离，从而减轻α-突触核蛋白聚集、神经变性以及α-突触核蛋白预成纤维注射突触核蛋白病小鼠的进行性运动障碍。因此，Ca2+流入诱导的RNA G-四联体组装加速了α-突触核蛋白的相变和聚集，有可能导致突触核蛋白病。