title: Disruption of nongenomic testosterone signaling in a model of spinal and bulbar muscular atrophy.
abstract: As one of the nine hereditary neurodegenerative polyQ disorders, spinal and bulbar muscular atrophy (SBMA) results from a polyQ tract expansion in androgen receptor (AR). Although protein aggregates are the pathological hallmark of many neurodegenerative diseases, their direct role in the neurodegeneration is more and more questioned. To determine the early molecular mechanisms causing motor neuron degeneration in SBMA, we established an in vitro system based on the tetracycline-inducible expression of normal (AR20Q), the mutated, 51 glutamine-extended (AR51Q), or polyQ-deleted (AR0Q) AR in NSC34, a motor neuron-like cell line lacking endogenous AR. Although no intracellular aggregates were formed, the expression of the AR51Q leads to a loss of function characterized by reduced neurite outgrowth and to a toxic gain of function resulting in decreased cell viability. In this study, we show that both AR20Q and AR51Q are recruited to lipid rafts in response to testosterone stimulation. However, whereas testosterone induces the activation of the c-jun N-terminal kinase/c-jun pathway via membrane-associated AR20Q, it does not so in NSC34 expressing AR51Q. Phosphorylation of c-jun N-terminal kinase plays a crucial role in AR20Q-dependent survival and differentiation of NSC34. Moreover, c-jun protein levels decrease more slowly in AR20Q- than in AR51Q-expressing NSC34 cells. This is due to a rapid and transient inhibition of glycogen synthase kinase 3α occurring in a phosphatidylinositol 3-kinase-independent manner. Our results demonstrate that the deregulation of nongenomic AR signaling may be involved in SBMA establishment, opening new therapeutic perspectives.
authors.affiliation: Institut des Neurosciences de Montpellier, Institut National de la Santé et de la Recherche Médicale Unité 1051, 34295 Montpellier, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Schindler
authors.forename: Christine
authors.initials: C
authors.lastname: Fabre
authors.forename: Jan
authors.initials: J
authors.lastname: de Weille
authors.forename: Serge
authors.initials: S
authors.lastname: Carreau
authors.forename: Marcel
authors.initials: M
authors.lastname: Mersel
authors.forename: Norbert
authors.initials: N
authors.lastname: Bakalara
mesh_terms: D000818:Animals; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D020966:Muscular Disorders, Atrophic / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism*
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D013739:Testosterone; D058539:Phosphatidylinositol 3-Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha