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

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 journal › Article › peer-review

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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 language	English
Article number	eabd9440
Journal	Science Advances
Volume	7
Issue number	3
DOIs	https://doi.org/10.1126/sciadv.abd9440
Publication status	Published - 2021 Jan 13
Externally published	Yes

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Asamitsu, S., Yabuki, Y., Ikenoshita, S., Kawakubo, K., Kawasaki, M., Usuki, S., Nakayama, Y., Adachi, K., Kugoh, H., Ishii, K., Matsuura, T., Nanba, E., Sugiyama, H., Fukunaga, K., & Shioda, N. (2021). CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. Science Advances, 7(3), [eabd9440]. https://doi.org/10.1126/sciadv.abd9440

CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. / Asamitsu, Sefan; Yabuki, Yasushi; Ikenoshita, Susumu; Kawakubo, Kosuke; Kawasaki, Moe; Usuki, Shingo; Nakayama, Yuji; Adachi, Kaori; Kugoh, Hiroyuki; Ishii, Kazuhiro; Matsuura, Tohru; Nanba, Eiji; Sugiyama, Hiroshi; Fukunaga, Kohji; Shioda, Norifumi.

In: Science Advances, Vol. 7, No. 3, eabd9440, 13.01.2021.

Research output: Contribution to journal › Article › peer-review

Asamitsu, S, Yabuki, Y, Ikenoshita, S, Kawakubo, K, Kawasaki, M, Usuki, S, Nakayama, Y, Adachi, K, Kugoh, H, Ishii, K, Matsuura, T, Nanba, E, Sugiyama, H, Fukunaga, K & Shioda, N 2021, 'CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome', Science Advances, vol. 7, no. 3, eabd9440. https://doi.org/10.1126/sciadv.abd9440

Asamitsu, Sefan ; Yabuki, Yasushi ; Ikenoshita, Susumu ; Kawakubo, Kosuke ; Kawasaki, Moe ; Usuki, Shingo ; Nakayama, Yuji ; Adachi, Kaori ; Kugoh, Hiroyuki ; Ishii, Kazuhiro ; Matsuura, Tohru ; Nanba, Eiji ; Sugiyama, Hiroshi ; Fukunaga, Kohji ; Shioda, Norifumi. / CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. In: Science Advances. 2021 ; Vol. 7, No. 3.

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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.",

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AU - Kawakubo, Kosuke

AU - Kawasaki, Moe

AU - Usuki, Shingo

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AU - Adachi, Kaori

AU - Kugoh, Hiroyuki

AU - Ishii, Kazuhiro

AU - Matsuura, Tohru

AU - Nanba, Eiji

AU - Sugiyama, Hiroshi

AU - Fukunaga, Kohji

AU - Shioda, Norifumi

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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.

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

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