Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy.
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 SBMA-iPSCs. 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 derived from SBMA-iPSCs, indicating a potential for discovery and validation of candidate drugs. We found 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.
Department of Neurologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Yoshihiro
Y
Nihei
Department of Neurologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: d-ito@jk9.so-net.ne.jp.
Daisuke
D
Ito
Physiologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan; Kanrinmaru Project, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Yohei
Y
Okada
Physiologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Wado
W
Akamatsu
Department of Neurologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Takuya
T
Yagi
Department of Neurologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Takahito
T
Yoshizaki
Physiologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Hideyuki
H
Okano
Department of Neurologyt, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Norihiro
N
Suzuki
D000369:Aged, 80 and over; D000728:Androgens / Q000494:pharmacology; D001483:Base Sequence; D016227:Benzoquinones / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D018911:Trinucleotide Repeats
D000728:Androgens; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D011944:Receptors, Androgen; C095278:atrophin-1; D013196:Dihydrotestosterone; C112765:tanespimycin