ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1
- Hideki Nishitoh1,2,3,
- Hisae Kadowaki1,2,3,4,5,
- Atsushi Nagai3,
- Takeshi Maruyama3,
- Takanori Yokota6,
- Hisashi Fukutomi1,4,5,
- Takuya Noguchi1,4,5,
- Atsushi Matsuzawa1,4,5,
- Kohsuke Takeda1,4,5, and
- Hidenori Ichijo1,4,5,7
- 1 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Bunkyo-ku, Tokyo 113-0033, Japan;
- 2 Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan;
- 3 Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan;
- 4 Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
- 5 Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence Program, Bunkyo-ku, Tokyo 113-0033, Japan;
- 6 Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
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 SOD1mut-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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Footnotes
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↵7 Corresponding author.
↵7 E-MAIL ichijo{at}mol.f.u-tokyo.ac.jp; FAX 81-3-5841-4778.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1640108.
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- Received December 5, 2007.
- Accepted April 11, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
