Protective effects of estrogens on polyglutamine-expanded androgen receptor aggregation in mice.
Spinal and bulbar muscular atrophy is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor (AR). Only males are affected as the development of pathology requires high levels of circulating androgens. Androgens promote aggregation of the AR into characteristic intracellular inclusions. As a potential factor contributing to the protection of female carriers, we assessed the effects of estrogens on AR aggregation in transfected neuronal cells using a filter retardation assay. Pre-treatment of mouse neuroblastoma Neuro2a cells expressing an AR with 51 glutamine residues with 10 microM 17beta- or 17alpha-estradiol prevented induction of AR aggregation by testosterone. Western blot analysis showed that the protective effects of estrogens occurred in the absence of a change in AR processing. We conclude that estrogens protect polyglutamine-expanded AR from aggregation through a non-genomic mechanism possibly involving estrogen binding to the AR.
Darrington
R Siobhan
RS
Department of Neurology, Institute of Psychiatry, King's College London, Box PO38, De Crespigny Park, London, SE5 8AF, UK.
Leigh
P Nigel
PN
Gallo
Jean-Marc
JM
D000818:Animals; D015153:Blotting, Western; D004347:Drug Interactions; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D011940:Receptor Aggregation / Q000187:drug effects*; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D019680:Trinucleotide Repeat Expansion; D014407:Tumor Cells, Cultured
D004967:Estrogens; D010455:Peptides; D020011:Protective Agents; D011944:Receptors, Androgen; C097188:polyglutamine; D013739:Testosterone