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

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

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

[Keywords: Amyotrophic lateral sclerosis; endoplasmic reticulum-associated degradation; endoplasmic reticulum stress; Derlin-1; ASK1]

Received December 5, 2007; revised version accepted April 11, 2008.

E-MAIL ichijo{at}mol.f.u-tokyo.ac.jp; FAX 81-3-5841-4778.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1640108.

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