期刊
NATURE MEDICINE
卷 18, 期 10, 页码 1531-U131出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2932
关键词
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资金
- Center-of-Excellence, Ministry of Education, Culture, Sports, Science and Technology, Japan [22110005, 21229011, 21689024, 23390230]
- Ministry of Health, Labor and Welfare, Japan
- Core Research for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency (JST)
- Kennedy Disease Association
- Grants-in-Aid for Scientific Research [23659107, 23013007, 23390230, 21689024, 21229011, 22110005] Funding Source: KAKEN
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 alpha (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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