| Literature DB >> 23023499 |
Makoto Minamiyama1, Masahisa Katsuno, Hiroaki Adachi, Hideki Doi, Naohide Kondo, Madoka Iida, Shinsuke Ishigaki, Yusuke Fujioka, Shinjiro Matsumoto, Yu Miyazaki, Fumiaki Tanaka, Hiroki Kurihara, Gen Sobue.
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.Entities:
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Year: 2012 PMID： 23023499 DOI： 10.1038/nm.2932
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440