QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 18, 2009, 29(7):1987-1997; doi:10.1523/JNEUROSCI.4072-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Young, J. E. Articles by La Spada, A. R. Search for Related Content PubMed PubMed Citation Articles by Young, J. E. Articles by La Spada, A. R.

 Previous Article  |  Next Article 

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

Jessica E. Young,^1 * Gwenn A. Garden,^2,5 * Refugio A. Martinez,¹ Fumiaki Tanaka,⁶ C. Miguel Sandoval,⁶ Annette C. Smith,¹ Bryce L. Sopher,¹ Amy Lin,⁷ Kenneth H. Fischbeck,⁶ Lisa M. Ellerby,⁷ Richard S. Morrison,^3,5 J. Paul Taylor,⁸ and Albert R. La Spada^1,2,4,5

Departments of ¹Laboratory Medicine, ²Neurology, ³Neurological Surgery, and ⁴Medicine, and ⁵Center for Neurogenetics and Neurotherapeutics, University of Washington, Seattle, Washington 98195-7110, ⁶Neurogenetics Branch, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, Maryland 20892, ⁷Buck Institute for Age Research, Novato, California 94945, and ⁸Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Albert R. La Spada, Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA 98195-7110. Email: laspada{at}u.washington.edu

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.

Key words: polyglutamine; spinal and bulbar muscular atrophy; truncation; apoptosis; Bax; DP5

---

Received Aug. 26, 2008; revised Nov. 26, 2008; accepted Dec. 31, 2008.

Correspondence should be addressed to Dr. Albert R. La Spada, Department of Laboratory Medicine, University of Washington Medical Center, Box 357110, Room NW 120, Seattle, WA 98195-7110. Email: laspada{at}u.washington.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help