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An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy.

Publication ,  Journal Article
Orr, CR; Montie, HL; Liu, Y; Bolzoni, E; Jenkins, SC; Wilson, EM; Joseph, JD; McDonnell, DP; Merry, DE
Published in: J Biol Chem
November 12, 2010

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function.

Duke Scholars

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 12, 2010

Volume

285

Issue

46

Start / End Page

35567 / 35577

Location

United States

Related Subject Headings

  • Two-Hybrid System Techniques
  • Trinucleotide Repeat Expansion
  • Tosyl Compounds
  • Testosterone
  • Receptors, Androgen
  • Rats
  • Protein Binding
  • PC12 Cells
  • Nitriles
  • Mutation
 

Citation

APA
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ICMJE
MLA
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Orr, C. R., Montie, H. L., Liu, Y., Bolzoni, E., Jenkins, S. C., Wilson, E. M., … Merry, D. E. (2010). An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J Biol Chem, 285(46), 35567–35577. https://doi.org/10.1074/jbc.M110.146845
Orr, Christopher R., Heather L. Montie, Yuhong Liu, Elena Bolzoni, Shannon C. Jenkins, Elizabeth M. Wilson, James D. Joseph, Donald P. McDonnell, and Diane E. Merry. “An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy.J Biol Chem 285, no. 46 (November 12, 2010): 35567–77. https://doi.org/10.1074/jbc.M110.146845.
Orr CR, Montie HL, Liu Y, Bolzoni E, Jenkins SC, Wilson EM, et al. An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J Biol Chem. 2010 Nov 12;285(46):35567–77.
Orr, Christopher R., et al. “An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy.J Biol Chem, vol. 285, no. 46, Nov. 2010, pp. 35567–77. Pubmed, doi:10.1074/jbc.M110.146845.
Orr CR, Montie HL, Liu Y, Bolzoni E, Jenkins SC, Wilson EM, Joseph JD, McDonnell DP, Merry DE. An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J Biol Chem. 2010 Nov 12;285(46):35567–35577.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 12, 2010

Volume

285

Issue

46

Start / End Page

35567 / 35577

Location

United States

Related Subject Headings

  • Two-Hybrid System Techniques
  • Trinucleotide Repeat Expansion
  • Tosyl Compounds
  • Testosterone
  • Receptors, Androgen
  • Rats
  • Protein Binding
  • PC12 Cells
  • Nitriles
  • Mutation