Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model

Minako Tateno, Hisako Sadakata, Mika Tanaka, Shigeyoshi Itohara, Ryong Moon Shin, Masami Miura, Masao Masuda, Toshihiko Aosaki, Makoto Urushitani, Hidemi Misawa, Ryosuke Takahashi

研究成果: Article

111 引用 (Scopus)

抄録

Mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregation has been suggested as responsible for amyotrophic lateral sclerosis (ALS), although the operative mediating factors are as yet unestablished. To evaluate the contribution of motoneuronal Ca2+ -permeable (GluR2 subunit-lacking) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, we generated chat-GluR2 transgenic mice with significantly reduced Ca2+ -permeability of these receptors in spinal motoneurons. Crossbreeding of the hSOD1G93A transgenic mouse model of ALS with chat-GluR2 mice led to marked delay of disease onset (19.5%), mortality (14.3%) and the pathological hallmarks such as release of cytochrome c from mitochondria, induction of cox2 and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species first accumulated in two fractions dense with neurofilaments/ glial fibrillary acidic protein/nuclei and mitochondria long time before disease onset, and then concentrated into the former fraction by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca2+ -influx through atypical motoneuronal AMPA receptors thus promotes a misfolding of mutant SOD1 protein and eventual death of these neurons.

元の言語English
ページ(範囲)2183-2196
ページ数14
ジャーナルHuman Molecular Genetics
13
発行部数19
DOI
出版物ステータスPublished - 2004 10 1
外部発表Yes

Fingerprint

AMPA Receptors
Amyotrophic Lateral Sclerosis
Mutant Proteins
Transgenic Mice
Calcium
Mitochondria
Genetic Hybridization
Isoxazoles
Intermediate Filaments
Glial Fibrillary Acidic Protein
Glutamate Receptors
Motor Neurons
Cytochromes c
Permeability
Neurons
Mortality
Superoxide Dismutase-1

ASJC Scopus subject areas

  • Genetics

これを引用

Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. / Tateno, Minako; Sadakata, Hisako; Tanaka, Mika; Itohara, Shigeyoshi; Shin, Ryong Moon; Miura, Masami; Masuda, Masao; Aosaki, Toshihiko; Urushitani, Makoto; Misawa, Hidemi; Takahashi, Ryosuke.

:: Human Molecular Genetics, 巻 13, 番号 19, 01.10.2004, p. 2183-2196.

研究成果: Article

Tateno, M, Sadakata, H, Tanaka, M, Itohara, S, Shin, RM, Miura, M, Masuda, M, Aosaki, T, Urushitani, M, Misawa, H & Takahashi, R 2004, 'Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model', Human Molecular Genetics, 巻. 13, 番号 19, pp. 2183-2196. https://doi.org/10.1093/hmg/ddh246
Tateno, Minako ; Sadakata, Hisako ; Tanaka, Mika ; Itohara, Shigeyoshi ; Shin, Ryong Moon ; Miura, Masami ; Masuda, Masao ; Aosaki, Toshihiko ; Urushitani, Makoto ; Misawa, Hidemi ; Takahashi, Ryosuke. / Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. :: Human Molecular Genetics. 2004 ; 巻 13, 番号 19. pp. 2183-2196.
@article{71e96e7ddeb142eeb9336c64684f0d27,
title = "Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model",
abstract = "Mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregation has been suggested as responsible for amyotrophic lateral sclerosis (ALS), although the operative mediating factors are as yet unestablished. To evaluate the contribution of motoneuronal Ca2+ -permeable (GluR2 subunit-lacking) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, we generated chat-GluR2 transgenic mice with significantly reduced Ca2+ -permeability of these receptors in spinal motoneurons. Crossbreeding of the hSOD1G93A transgenic mouse model of ALS with chat-GluR2 mice led to marked delay of disease onset (19.5{\%}), mortality (14.3{\%}) and the pathological hallmarks such as release of cytochrome c from mitochondria, induction of cox2 and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species first accumulated in two fractions dense with neurofilaments/ glial fibrillary acidic protein/nuclei and mitochondria long time before disease onset, and then concentrated into the former fraction by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca2+ -influx through atypical motoneuronal AMPA receptors thus promotes a misfolding of mutant SOD1 protein and eventual death of these neurons.",
author = "Minako Tateno and Hisako Sadakata and Mika Tanaka and Shigeyoshi Itohara and Shin, {Ryong Moon} and Masami Miura and Masao Masuda and Toshihiko Aosaki and Makoto Urushitani and Hidemi Misawa and Ryosuke Takahashi",
year = "2004",
month = "10",
day = "1",
doi = "10.1093/hmg/ddh246",
language = "English",
volume = "13",
pages = "2183--2196",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "19",

}

TY - JOUR

T1 - Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model

AU - Tateno, Minako

AU - Sadakata, Hisako

AU - Tanaka, Mika

AU - Itohara, Shigeyoshi

AU - Shin, Ryong Moon

AU - Miura, Masami

AU - Masuda, Masao

AU - Aosaki, Toshihiko

AU - Urushitani, Makoto

AU - Misawa, Hidemi

AU - Takahashi, Ryosuke

PY - 2004/10/1

Y1 - 2004/10/1

N2 - Mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregation has been suggested as responsible for amyotrophic lateral sclerosis (ALS), although the operative mediating factors are as yet unestablished. To evaluate the contribution of motoneuronal Ca2+ -permeable (GluR2 subunit-lacking) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, we generated chat-GluR2 transgenic mice with significantly reduced Ca2+ -permeability of these receptors in spinal motoneurons. Crossbreeding of the hSOD1G93A transgenic mouse model of ALS with chat-GluR2 mice led to marked delay of disease onset (19.5%), mortality (14.3%) and the pathological hallmarks such as release of cytochrome c from mitochondria, induction of cox2 and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species first accumulated in two fractions dense with neurofilaments/ glial fibrillary acidic protein/nuclei and mitochondria long time before disease onset, and then concentrated into the former fraction by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca2+ -influx through atypical motoneuronal AMPA receptors thus promotes a misfolding of mutant SOD1 protein and eventual death of these neurons.

AB - Mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregation has been suggested as responsible for amyotrophic lateral sclerosis (ALS), although the operative mediating factors are as yet unestablished. To evaluate the contribution of motoneuronal Ca2+ -permeable (GluR2 subunit-lacking) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors to SOD1-related motoneuronal death, we generated chat-GluR2 transgenic mice with significantly reduced Ca2+ -permeability of these receptors in spinal motoneurons. Crossbreeding of the hSOD1G93A transgenic mouse model of ALS with chat-GluR2 mice led to marked delay of disease onset (19.5%), mortality (14.3%) and the pathological hallmarks such as release of cytochrome c from mitochondria, induction of cox2 and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species first accumulated in two fractions dense with neurofilaments/ glial fibrillary acidic protein/nuclei and mitochondria long time before disease onset, and then concentrated into the former fraction by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca2+ -influx through atypical motoneuronal AMPA receptors thus promotes a misfolding of mutant SOD1 protein and eventual death of these neurons.

UR - http://www.scopus.com/inward/record.url?scp=5444222849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=5444222849&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddh246

DO - 10.1093/hmg/ddh246

M3 - Article

C2 - 15294873

AN - SCOPUS:5444222849

VL - 13

SP - 2183

EP - 2196

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 19

ER -