title: Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk.
abstract: Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) repeat expansion in the androgen receptor (AR). PolyQ-AR neurotoxicity may involve generation of an N-terminal truncation fragment, as such peptides occur in SBMA patients and mouse models. To elucidate the basis of SBMA, we expressed N-terminal truncated AR in motor neuron-derived cells and primary cortical neurons. Accumulation of polyQ-AR truncation fragments in the cytosol resulted in neurodegeneration and apoptotic, caspase-dependent cell death. Using primary neurons from mice transgenic or deficient for apoptosis-related genes, we determined that polyQ-AR apoptotic activation is fully dependent on Bax. Jun N-terminal kinase (JNK) was required for apoptotic pathway activation through phosphorylation of c-Jun. Expression of polyQ-AR in DP5/Hrk null neurons yielded significant protection against apoptotic activation, but absence of Bim did not provide protection, apparently due to compensatory upregulation of DP5/Hrk or other BH3-only proteins. Misfolded AR protein in the cytosol thus initiates a cascade of events beginning with JNK and culminating in Bax-dependent, intrinsic pathway activation, mediated in part by DP5/Hrk. As apoptotic mediators are candidates for toxic fragment generation and other cellular processes linked to neuron dysfunction, delineation of the apoptotic activation pathway induced by polyQ-expanded AR may shed light on the pathogenic cascade in SBMA and other motor neuron diseases.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195-7110, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Young
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.forename: Refugio A
authors.initials: RA
authors.lastname: Martinez
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: C Miguel
authors.initials: CM
authors.lastname: Sandoval
authors.forename: Annette C
authors.initials: AC
authors.lastname: Smith
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D017510:Protein Folding; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; C107631:Hrk protein, mouse; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D011944:Receptors, Androgen; D051028:bcl-2-Associated X Protein; C097188:polyglutamine; D048031:JNK Mitogen-Activated Protein Kinases