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Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by an expanded polyglutamine repeat tract

Nature Medicine volume 18, pages 1531–1538 (2012)Cite this article

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Abstract

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.

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Figure 1: Upregulation of CGRP1 in AR-97Q mice and patients with SBMA.
Figure 2: Neurotoxicity of CGRP1 in a cellular model of SBMA.
Figure 3: CGRP1 induces neuronal cell damage via activation of the JNK pathway.
Figure 4: Deletion of CGRP1 attenuates symptoms and histopathology in SBMA mice (a) Rotarod task, grip strength, body weight and survival rate of wild-type (n = 15), AR-97Q (n = 16) and AR-97Q Calca−/− (n = 16) mice.
Figure 5: Naratriptan downregulates CGRP1 and mitigates the toxicity of pathogenic AR.
Figure 6: Oral naratriptan attenuates the symptoms and histopathology, and inhibits the JNK pathway in SBMA mice.

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Acknowledgements

This work was supported by a Center-of-Excellence grant, a Grant-in-Aid for Scientific Research on Innovated Areas “Foundation of Synapse and Neurocircuit Pathology” (No. 22110005) and Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Nos. 21229011, 21689024 and 23390230); grants from the Ministry of Health, Labor and Welfare, Japan; Core Research for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency (JST); and a grant from the Kennedy Disease Association.

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  1. Makoto Minamiyama and Masahisa Katsuno: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Makoto Minamiyama, Masahisa Katsuno, Hiroaki Adachi, Hideki Doi, Naohide Kondo, Madoka Iida, Shinsuke Ishigaki, Yusuke Fujioka, Shinjiro Matsumoto, Yu Miyazaki, Fumiaki Tanaka & Gen Sobue

  2. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Hiroki Kurihara

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Contributions

Project planning was performed by M.M., M.K., H.K. and G.S.; microarray analysis by M.M. and M.K.; cellular analysis by M.M., M.K., H.A., H.D., S.M. and Y.M.; primary motor neuron culture by M.K., S.I. and Y.F.; animal work by M.M., M.K., N.K. and M.I.; tissue staining by M.M., M.K. and M.I.; and data analysis by M.M., M.K., F.T. and G.S. M.M. and M.K. drafted the manuscript, and F.T., H.K. and G.S. revised it critically for intellectual content.

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Correspondence to Masahisa Katsuno or Gen Sobue.

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Minamiyama, M., Katsuno, M., Adachi, H. et al. Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by an expanded polyglutamine repeat tract. Nat Med 18, 1531–1538 (2012). https://doi.org/10.1038/nm.2932

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