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.

• Authors: 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
• Journal: Science advances (Sci Adv) Vol. 7 Issue 3 (01 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 33523882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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).

Chemical References

• Fmr1 protein, mouse
• Fragile X Mental Retardation Protein

Topics

• Animals
• Ataxia (genetics, metabolism, pathology)
• Fragile X Mental Retardation Protein (genetics)
• Fragile X Syndrome (genetics)
• G-Quadruplexes
• Mice
• Neurodegenerative Diseases
• Tremor (genetics, metabolism)