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

Autor:	Matsuo K; 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., Asamitsu S; 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., Maeda K; 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., Suzuki H; Department of Pathology and Laboratory Medicine, National Hospital Organization Sendai Medical Center, Sendai 983-8520, Japan., Kawakubo K; 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., Komiya G; 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., Kudo K; 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., Sakai Y; 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., Hori K; Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan., Ikenoshita S; 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., Usuki S; Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan., Funahashi S; Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan., Oizumi H; Department of Neurology, National Hospital Organization Sendai Nishitaga Hospital, Sendai 982-8555, Japan., Takeda A; Department of Neurology, National Hospital Organization Sendai Nishitaga Hospital, Sendai 982-8555, Japan., Kawata Y; Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan., Mizobata T; Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan., Shioda N; 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., Yabuki Y; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1016/j.cell.2024.09.037
Abstrakt:	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 Ca 2+ -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 Ca 2+ 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, Ca 2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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