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

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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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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