| First Author | Matsuo K | Year | 2024 |
| Journal | Cell | PubMed ID | 39426376 |
| Mgi Jnum | J:358174 | Mgi Id | MGI:7779267 |
| Doi | 10.1016/j.cell.2024.09.037 | Citation | Matsuo K, et al. (2024) RNA G-quadruplexes form scaffolds that promote neuropathological alpha-synuclein aggregation. Cell |
| abstractText | Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by alpha-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular alpha-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for alpha-synuclein aggregation, contributing to neurodegeneration. Purified alpha-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca(2+)-induced phase separation and assembly, accelerating alpha-synuclein sol-gel phase transition. In alpha-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with alpha-synuclein upon excess cytoplasmic Ca(2+) influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes alpha-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 alpha-synuclein aggregation, neurodegeneration, and progressive motor deficits in alpha-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca(2+) influx-induced RNA G-quadruplex assembly accelerates alpha-synuclein phase transition and aggregation, potentially contributing to synucleinopathies. |
