Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy

Yoshihiro Nihei, Daisuke Ito, Yohei Okada, Wado Akamatsu, Takuya Yagi, Takahito Yoshizaki, Hideyuki Okano, Norihiro Suzuki

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. Ligand-dependent nuclear accumulation of mutant AR protein is a critical characteristic of the pathogenesis of SBMA. SBMA has been modeled in AR-overexpressing animals, but precisely how the polyglutamine (polyQ) expansion leads to neurodegeneration is unclear. Induced pluripotent stem cells (iPSCs) are a new technology that can be used to model human diseases, study pathogenic mechanisms, and develop novel drugs. We established SBMA patient-derived iPSCs, investigated their cellular biochemical characteristics, and found that SBMA-iPSCs can differentiate into motor neurons. The CAG repeat numbers in the AR gene of SBMA-iPSCs and also in the atrophin-1 gene of iPSCs derived from another polyQ disease, dentato-rubro-pallido-luysian atrophy (DRPLA), remain unchanged during reprogramming, long term passage, and differentiation, indicating that polyQ disease-associated CAG repeats are stable during maintenance of iPSCs. The level of AR expression is up-regulated by neuronal differentiation and treatment with the AR ligand dihydrotestosterone. Filter retardation assays indicated that aggregation of ARs following dihydrotestosterone treatment in neurons derived from SBMA-iPSCs increases significantly compared with neurological control iPSCs, easily recapitulating the pathological feature of mutant ARs in SBMAiPSCs. This phenomenon was not observed in iPSCs and fibroblasts, thereby showing the neuron-dominant phenotype of this disease. Furthermore, the HSP90 inhibitor 17-allylaminogeldanamycin sharply decreased the level of aggregated AR in neurons derivedfromSBMA-iPSCs, indicatingapotentialfordiscoveryand validation of candidate drugs.Wefound that SBMA-iPSCs possess disease-specific biochemical features and could thus open new avenues of research into not only SBMA, but also other polyglutamine diseases.

Original languageEnglish
Pages (from-to)8043-8052
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number12
DOIs
Publication statusPublished - 2013 Mar 22

Fingerprint

Atrophic Muscular Disorders
Induced Pluripotent Stem Cells
Androgen Receptors
Stem cells
Neurons
Agglomeration
Dihydrotestosterone
Genes
tanespimycin
X-Linked Bulbo-Spinal Atrophy
Ligands
Motor Neuron Disease
Motor Neurons
Fibroblasts
Pharmaceutical Preparations
Atrophy
Assays
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy. / Nihei, Yoshihiro; Ito, Daisuke; Okada, Yohei; Akamatsu, Wado; Yagi, Takuya; Yoshizaki, Takahito; Okano, Hideyuki; Suzuki, Norihiro.

In: Journal of Biological Chemistry, Vol. 288, No. 12, 22.03.2013, p. 8043-8052.

Research output: Contribution to journalArticle

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AU - Suzuki, Norihiro

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