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Updated: Jun 10, 2025
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Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
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RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation
Kazuya Matsuo1, Sefan Asamitsu2, Kohei Maeda1
1Department 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.
Cell
|October 19, 2024
Summary
RNA G-quadruplexes scaffold alpha-synuclein aggregation, driving neurodegeneration in synucleinopathies like Parkinson's disease. This process, triggered by calcium influx, is preventable with 5-aminolevulinic acid.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Synucleinopathies, such as Parkinson's disease, are characterized by alpha-synuclein aggregation and neurodegeneration.
- The precise intracellular mechanisms driving alpha-synuclein aggregation remain incompletely understood.
Purpose of the Study:
- To investigate the role of RNA G-quadruplexes in alpha-synuclein aggregation and neurodegeneration.
- To explore potential therapeutic strategies targeting RNA G-quadruplex-mediated aggregation.
Main Methods:
- In vitro binding assays of purified alpha-synuclein with RNA G-quadruplexes.
- Calcium-induced phase separation and assembly studies of RNA G-quadruplexes and alpha-synuclein.
- Neuronal cell culture models treated with alpha-synuclein preformed fibrils and subjected to calcium influx.
- Optogenetic manipulation to induce RNA G-quadruplex assembly.
- In vivo studies using synucleinopathic mouse models treated with 5-aminolevulinic acid.
Main Results:
- Purified alpha-synuclein directly binds to RNA G-quadruplexes via its N-terminus.
- RNA G-quadruplexes promote alpha-synuclein aggregation and accelerate its phase transition.
- Excess cytoplasmic calcium influx induces co-aggregation of synaptic mRNAs and alpha-synuclein, leading to synaptic dysfunction.
- Optogenetically induced RNA G-quadruplex assembly causes neuronal dysfunction and neurodegeneration.
- 5-aminolevulinic acid treatment inhibits RNA G-quadruplex phase separation, reducing alpha-synuclein aggregation and neurodegeneration in mice, and improving motor deficits.
Conclusions:
- Calcium influx-induced RNA G-quadruplex assembly acts as a scaffold, accelerating alpha-synuclein aggregation and contributing to synucleinopathies.
- Targeting RNA G-quadruplex phase separation presents a potential therapeutic avenue for synucleinopathies.
