title: Characterization of an expanded glutamine repeat androgen receptor in a neuronal cell culture system.
abstract: Spinal and bulbar muscular atrophy (SBMA) is an inherited form of lower motor neuron degeneration caused by expansion of a CAG repeat in the androgen receptor (AR) gene. To study the mechanism by which this mutation causes neuronal pathology, we stably transfected a motor neuron hybrid cell line with human AR cDNAs containing either 24 or 65 repeats (AR24 and AR65, respectively). Both forms of receptor were able to bind ligand and activate transcription of a reporter construct equally well. Likewise, the subcellular localizations of AR24 and AR65 were similar, in both the presence and the absence of ligand. AR24- and AR65-expressing clones were phenotypically indistinguishable. They survived equally well after differentiation and were equally susceptible to damage by oxidative stress. Our studies thus demonstrate that, in a neuronal system, the expanded repeat AR functions like the normal repeat AR in several important ways. Because levels of AR65 expression were consistently lower than levels of AR24 expression, we propose that the loss of function of AR seen in SBMA may be due to decreased levels of receptor expression rather than to a difference in intrinsic properties. The postulated gain of function responsible for neuronal degeneration remains to be determined.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Room 250 CRB, 415 Curie Boulevard, Philadelphia, Pennsylvania, 19104, USA. bpbrooks@mail.med.upenn.edu
authors.forename: B P
authors.initials: BP
authors.lastname: Brooks
authors.forename: H L
authors.initials: HL
authors.lastname: Paulson
authors.forename: D E
authors.initials: DE
authors.lastname: Merry
authors.forename: E F
authors.initials: EF
authors.lastname: Salazar-Grueso
authors.forename: A O
authors.initials: AO
authors.lastname: Brinkmann
authors.forename: E M
authors.initials: EM
authors.lastname: Wilson
authors.forename: K H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D018076:DNA, Complementary / Q000235:genetics; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D051379:Mice / Q000196:embryology; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D011944:Receptors, Androgen; D005973:Glutamine