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

被引：32

作者：

Minamiyama, Makoto ^{[1
]}

Katsuno, Masahisa ^{[1
]}

Adachi, Hiroaki ^{[1
]}

Doi, Hideki ^{[1
]}

Kondo, Naohide ^{[1
]}

Iida, Madoka ^{[1
]}

Ishigaki, Shinsuke ^{[1
]}

Fujioka, Yusuke ^{[1
]}

Matsumoto, Shinjiro ^{[1
]}

Miyazaki, Yu ^{[1
]}

Tanaka, Fumiaki ^{[1
]}

Kurihara, Hiroki ^{[2
]}

Sobue, Gen ^{[1
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4648601, Japan

[2] Univ Tokyo, Grad Sch Med, Dept Physiol Chem & Metab, Tokyo, Japan

来源：

NATURE MEDICINE | 2012年 / 18卷 / 10期

基金：

日本科学技术振兴机构;

关键词：

BULBAR MUSCULAR-ATROPHY; GENE-RELATED PEPTIDE; TRANSGENIC MOUSE MODEL; HISTONE DEACETYLASE INHIBITORS; MUTANT ANDROGEN RECEPTOR; HUNTINGTONS-DISEASE; DEPENDENT NEURODEGENERATION; PHENOTYPIC-EXPRESSION; AXONAL-TRANSPORT; PROTEIN-KINASE;

D O I：

10.1038/nm.2932

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1531 / U131

页数：10

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