ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1

Hideki Nishitoh, Hisae Kadowaki, Atsushi Nagai, Takeshi Maruyama, Takanori Yokota, Hisashi Fukutomi, Takuya Noguchi, Atsushi Matsuzawa, Kohsuke Takeda, Hidenori Ichijo

研究成果: Article

317 引用 (Scopus)

抄録

Mutation in Cu/Zn-superoxide dismutase (SOD1) is a cause of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein (SOD1mut) induces motor neuron death, although the molecular mechanism of SOD1 mut-induced cell death remains controversial. Here we show that SOD1mut specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. SOD1mut-induced ER stress activated the apoptosis signal-regulating kinase 1 (ASK1)-dependent cell death pathway. Perturbation of binding between SOD1mut and Derlin-1 by Derlin-1-derived oligopeptide suppressed SOD1mut-induced ER stress, ASK1 activation, and motor neuron death. Moreover, deletion of ASK1 mitigated the motor neuron loss and extended the life span of SOD1mut transgenic mice. These findings demonstrate that ER stress-induced ASK1 activation, which is triggered by the specific interaction of Derlin-1 with SOD1mut, is crucial for disease progression of familial ALS.

元の言語English
ページ(範囲)1451-1464
ページ数14
ジャーナルGenes and Development
22
発行部数11
DOI
出版物ステータスPublished - 2008 6 1
外部発表Yes

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MAP Kinase Kinase Kinase 5
Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Motor Neurons
Cell Death
Endoplasmic Reticulum-Associated Degradation
Oligopeptides
Mutant Proteins
Transgenic Mice
Disease Progression
Mutation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

これを引用

ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. / Nishitoh, Hideki; Kadowaki, Hisae; Nagai, Atsushi; Maruyama, Takeshi; Yokota, Takanori; Fukutomi, Hisashi; Noguchi, Takuya; Matsuzawa, Atsushi; Takeda, Kohsuke; Ichijo, Hidenori.

:: Genes and Development, 巻 22, 番号 11, 01.06.2008, p. 1451-1464.

研究成果: Article

Nishitoh, H, Kadowaki, H, Nagai, A, Maruyama, T, Yokota, T, Fukutomi, H, Noguchi, T, Matsuzawa, A, Takeda, K & Ichijo, H 2008, 'ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1', Genes and Development, 巻. 22, 番号 11, pp. 1451-1464. https://doi.org/10.1101/gad.1640108
Nishitoh, Hideki ; Kadowaki, Hisae ; Nagai, Atsushi ; Maruyama, Takeshi ; Yokota, Takanori ; Fukutomi, Hisashi ; Noguchi, Takuya ; Matsuzawa, Atsushi ; Takeda, Kohsuke ; Ichijo, Hidenori. / ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. :: Genes and Development. 2008 ; 巻 22, 番号 11. pp. 1451-1464.
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abstract = "Mutation in Cu/Zn-superoxide dismutase (SOD1) is a cause of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein (SOD1mut) induces motor neuron death, although the molecular mechanism of SOD1 mut-induced cell death remains controversial. Here we show that SOD1mut specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. SOD1mut-induced ER stress activated the apoptosis signal-regulating kinase 1 (ASK1)-dependent cell death pathway. Perturbation of binding between SOD1mut and Derlin-1 by Derlin-1-derived oligopeptide suppressed SOD1mut-induced ER stress, ASK1 activation, and motor neuron death. Moreover, deletion of ASK1 mitigated the motor neuron loss and extended the life span of SOD1mut transgenic mice. These findings demonstrate that ER stress-induced ASK1 activation, which is triggered by the specific interaction of Derlin-1 with SOD1mut, is crucial for disease progression of familial ALS.",
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