TY - JOUR
T1 - CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome
AU - Asamitsu, Sefan
AU - Yabuki, Yasushi
AU - Ikenoshita, Susumu
AU - Kawakubo, Kosuke
AU - Kawasaki, Moe
AU - Usuki, Shingo
AU - Nakayama, Yuji
AU - Adachi, Kaori
AU - Kugoh, Hiroyuki
AU - Ishii, Kazuhiro
AU - Matsuura, Tohru
AU - Nanba, Eiji
AU - Sugiyama, Hiroshi
AU - Fukunaga, Kohji
AU - Shioda, Norifumi
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/1/13
Y1 - 2021/1/13
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abd9440
DO - 10.1126/sciadv.abd9440
M3 - Article
C2 - 33523882
AN - SCOPUS:85099906383
VL - 7
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 3
M1 - eabd9440
ER -