Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors

被引：26

作者：

Iida, Madoka ^{[1
]}

Katsuno, Masahisa ^{[1
]}

Nakatsuji, Hideaki ^{[1
]}

Adachi, Hiroaki ^{[1
]}

Kondo, Naohide ^{[1
]}

Miyazaki, Yu ^{[1
]}

Tohnai, Genki ^{[1
]}

Ikenaka, Kensuke ^{[1
]}

Watanabe, Hirohisa ^{[1
]}

Yamamoto, Masahiko ^{[2
]}

Kishida, Ken ^{[3
,4
]}

Sobue, Gen ^{[1
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4668550, Japan

[2] Aichi Gakuin Univ, Sch Hlth Sci, Dept Speech Pathol & Audiol, Nisshin, Aichi 4700195, Japan

[3] Osaka Univ, Grad Sch Med, Dept Metab Med, Suita, Osaka 5650871, Japan

[4] Kishida Clin, Toyonaka, Osaka 5600021, Japan

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 02期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC MOUSE MODEL; NF-KAPPA-B; GAMMA PPAR-GAMMA; MITOCHONDRIAL DYSFUNCTION; HUNTINGTONS-DISEASE; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; INHERITED ALS; MOTOR-NEURONS;

D O I：

10.1093/hmg/ddu445

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 neuromuscular disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. Mutant AR has been postulated to alter the expression of genes important for mitochondrial function and induce mitochondrial dysfunction. Here, we show that the expression levels of peroxisome proliferator-activated receptor-gamma (PPAR gamma), a key regulator of mitochondrial biogenesis, were decreased in mouse and cellular models of SBMA. Treatment with pioglitazone (PG), an activator of PPAR gamma, improved the viability of the cellular model of SBMA. The oral administration of PG also improved the behavioral and histopathological phenotypes of the transgenic mice. Furthermore, immunohistochemical and biochemical analyses demonstrated that the administration of PG suppressed oxidative stress, nuclear factor-kappa B (NF kappa B) signal activation and inflammation both in the spinal cords and skeletal muscles of the SBMA mice. These findings suggest that PG is a promising candidate for the treatment of SBMA.

引用

页码：314 / 329

页数：16

共 66 条

[1] CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model [J].