Ligand-dependent aggregation of polyglutamine-expanded androgen receptor in neuronal cells.
Spinal and bulbar muscular atrophy (SBMA) is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor that forms characteristic inclusions in affected neurons. In order to assess the role of ligand binding in androgen receptor aggregation, we examined the distribution of an androgen receptor with 51 glutamine residues in transfected mouse neuroblastoma cells treated with androgens and antiandrogens. Stimulation with testosterone of cells grown in depleted medium or exposed to tamoxifen, resulted in the aggregation of the expanded androgen receptor into characteristic cytoplasmic inclusions. By contrast, very few aggregates were obtained after treatment with cyproterone acetate and none after treatment with flutamide. Furthermore, aggregation was not correlated with an overt change in accumulation of smaller androgen receptor species. Differential modulation of polyglutamine-expanded androgen receptor aggregation by ligands in neuronal cells may partly explain the absence of an overt disease phenotype in female carriers of the SBMA mutation and define conditions to explore further the role of androgen receptor aggregation in the pathogenesis of SBMA.
Darrington
R Siobhan
RS
Department of Neurology, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
Butler
Rachel
R
Leigh
P Nigel
PN
McPhaul
Michael J
MJ
Gallo
Jean-Marc
JM
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017373:Cyproterone Acetate / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D009133:Muscular Atrophy / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
D000726:Androgen Antagonists; D004965:Estrogen Antagonists; D008024:Ligands; D010455:Peptides; D011944:Receptors, Androgen; D013629:Tamoxifen; C097188:polyglutamine; D013739:Testosterone; D017373:Cyproterone Acetate; D005485:Flutamide