Back to Search
Start Over
Polyglutamine-Expanded Androgen Receptor Truncation Fragments Activate a Bax-Dependent Apoptotic Cascade Mediated by DP5/Hrk
- Source :
- The Journal of Neuroscience. 29:1987-1997
- Publication Year :
- 2009
- Publisher :
- Society for Neuroscience, 2009.
-
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.
- Subjects :
- Central Nervous System
Protein Folding
Programmed cell death
Apoptosis
Mice, Transgenic
Biology
Article
Cell Line
Muscular Atrophy, Spinal
Mice
Downregulation and upregulation
medicine
Animals
Cells, Cultured
bcl-2-Associated X Protein
Neurons
Kinase
General Neuroscience
Neuropeptides
Neurodegeneration
JNK Mitogen-Activated Protein Kinases
Motor neuron
medicine.disease
Molecular biology
Peptide Fragments
Cell biology
Androgen receptor
Spinal and bulbar muscular atrophy
medicine.anatomical_structure
Receptors, Androgen
Neuron
Apoptosis Regulatory Proteins
Peptides
Trinucleotide Repeat Expansion
Signal Transduction
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....c7175f21b1ee01f4c596314395f328f7