CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome

Sefan Asamitsu; Yasushi Yabuki; Susumu Ikenoshita; Kosuke Kawakubo; Moe Kawasaki; Shingo Usuki; Yuji Nakayama; Kaori Adachi; Hiroyuki Kugoh; Kazuhiro Ishii; Tohru Matsuura; Eiji Nanba; Hiroshi Sugiyama; Kohji Fukunaga; Norifumi Shioda

doi:10.1126/sciadv.abd9440

CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome

Sci Adv. 2021 Jan 13;7(3):eabd9440. doi: 10.1126/sciadv.abd9440. Print 2021 Jan.

Authors

Sefan Asamitsu¹, Yasushi Yabuki^{1

2}, Susumu Ikenoshita^{1

3}, Kosuke Kawakubo^{1

2}, Moe Kawasaki^{1

2}, Shingo Usuki⁴, Yuji Nakayama⁵, Kaori Adachi⁶, Hiroyuki Kugoh^{7

8}, Kazuhiro Ishii⁹, Tohru Matsuura¹⁰, Eiji Nanba¹¹, Hiroshi Sugiyama¹², Kohji Fukunaga¹³, Norifumi Shioda^{14

2}

Affiliations

¹ Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.
² Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
³ Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁴ Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.
⁵ Division of Radioisotope Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
⁶ Division of Genomic Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
⁷ Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori, Japan.
⁸ Chromosome Engineering Research Center, Tottori University, Tottori, Japan.
⁹ Department of the Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
¹⁰ Division of Neurology, Department of Medicine, Jichi Medical University, Shimono, Japan.
¹¹ Office for Research Strategy, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
¹² Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.
¹³ Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
¹⁴ Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan. shioda@kumamoto-u.ac.jp.

Abstract

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA-induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ataxia / genetics
Ataxia / metabolism
Ataxia / pathology
Fragile X Mental Retardation Protein / genetics
Fragile X Syndrome* / genetics
G-Quadruplexes*
Mice
Neurodegenerative Diseases*
Tremor / genetics
Tremor / metabolism

Substances

Fmr1 protein, mouse
Fragile X Mental Retardation Protein

Supplementary concepts

Fragile X Tremor Ataxia Syndrome