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

Madoka Iida, Masahisa Katsuno, Hideaki Nakatsuji, Hiroaki Adachi, Naohide Kondo, Yu Miyazaki, Genki Tohnai, Kensuke Ikenaka, Hirohisa Watanabe, Masahiko Yamamoto, Ken Kishida, Gen Sobue

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21 Citations (Scopus)

Abstract

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-γ (PPARγ), a key regulator of mitochondrial biogenesis, were decreased in mouse and cellular models of SBMA. Treatment with pioglitazone (PG), an activator of PPARγ, 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-κB (NFκB) 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.

Original languageEnglish
Article numberddu445
Pages (from-to)314-329
Number of pages16
JournalHuman molecular genetics
Volume24
Issue number2
DOIs
Publication statusPublished - 15-01-2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Iida, M., Katsuno, M., Nakatsuji, H., Adachi, H., Kondo, N., Miyazaki, Y., Tohnai, G., Ikenaka, K., Watanabe, H., Yamamoto, M., Kishida, K., & Sobue, G. (2015). Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors. Human molecular genetics, 24(2), 314-329. [ddu445]. https://doi.org/10.1093/hmg/ddu445