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

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.

SUBMITTER: Asamitsu S 

PROVIDER: S-EPMC7806243 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Asamitsu Sefan S   Yabuki Yasushi Y   Ikenoshita Susumu S   Kawakubo Kosuke K   Kawasaki Moe M   Usuki Shingo S   Nakayama Yuji Y   Adachi Kaori K   Kugoh Hiroyuki H   Ishii Kazuhiro K   Matsuura Tohru T   Nanba Eiji E   Sugiyama Hiroshi H   Fukunaga Kohji K   Shioda Norifumi N  

Science advances 20210113 3

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in <i>FMR1</i>, 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 wit  ...[more]

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