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

Makoto Minamiyama | Zendy; Masahisa Katsuno | Zendy; Hiroaki Adachi | Zendy; Hideki Doi | Zendy; Naohide Kondo | Zendy; Madoka Iida | Zendy; Shinsuke Ishigaki | Zendy; Yusuke Fujioka | Zendy; Shinjiro Matsumoto | Zendy; Yu Miyazaki | Zendy; Fumiaki Tanaka | Zendy; Hiroki Kurihara | Zendy; Gen Sobue | Zendy

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

Author(s) -

Makoto Minamiyama,

Masahisa Katsuno,

Hiroaki Adachi,

Hideki Doi,

Naohide Kondo,

Madoka Iida,

Shinsuke Ishigaki,

Yusuke Fujioka,

Shinjiro Matsumoto,

Yu Miyazaki,

Fumiaki Tanaka,

Hiroki Kurihara,

Gen Sobue

Publication year - 2012

Publication title -

nature medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.536

H-Index - 547

eISSN - 1546-170X

pISSN - 1078-8956

DOI - 10.1038/nm.2932

Subject(s) - spinal and bulbar muscular atrophy , neurodegeneration , androgen receptor , agonist , polyglutamine tract , motor neuron , biology , kinase , receptor , cancer research , microbiology and biotechnology , gene , medicine , neuroscience , spinal cord , huntingtin , biochemistry , genetics , disease , prostate cancer , cancer , mutant

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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