Polyglutamine-Expanded Androgen Receptor Truncation Fragments Activate a Bax-Dependent Apoptotic Cascade Mediated by DP5/Hrk

• DOI: 10.1523/jneurosci.4072-08.2009
• Publication Date: 2009-02-19T20:03:45Z
• Authors: Jessica E. Young; Gwenn A. Garden; Refugio A. Martinez; Fumiaki Tanaka; C. Miguel Sandoval; Annette C. Smith; Bryce L. Sopher; Amy Lin; Kenneth H. Fischbeck; Lisa M. Ellerby; Richard S. Morrison; J. Paul Taylor; Albert R. La Spada
• Keywords: Central Nervous System; Neurons; 0301 basic medicine; Protein Folding; Neuropeptides; JNK Mitogen-Activated Protein Kinases; Apoptosis; Mice, Transgenic; Peptide Fragments; Cell Line; Muscular Atrophy, Spinal; Mice; 03 medical and health sciences; Receptors, Androgen; Animals; Apoptosis Regulatory Proteins; Peptides; Trinucleotide Repeat Expansion; Cells, Cultured; Signal Transduction; bcl-2-Associated X Protein

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.