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

PHA - Life and Pharmaceutical Science

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

18 Citations (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 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

ASJC Scopus subject areas

General

Access to Document

10.1126/sciadv.abd9440

Cite this

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.

@article{ff04fb1f067740c5a690619ec45f2842,

title = "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.",

author = "Sefan Asamitsu and Yasushi Yabuki and Susumu Ikenoshita and Kosuke Kawakubo and Moe Kawasaki and Shingo Usuki and Yuji Nakayama and Kaori Adachi and Hiroyuki Kugoh and Kazuhiro Ishii and Tohru Matsuura and Eiji Nanba and Hiroshi Sugiyama and Kohji Fukunaga and Norifumi Shioda",

year = "2021",

month = jan,

day = "13",

doi = "10.1126/sciadv.abd9440",

language = "English",

volume = "7",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "3",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85099906383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85099906383&partnerID=8YFLogxK

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 -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this