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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article numbereabd9440
JournalScience Advances
Volume7
Issue number3
DOIs
Publication statusPublished - 2021 Jan 13
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome'. Together they form a unique fingerprint.

Cite this