An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy.
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.
Orr
Christopher R
CR
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Montie
Heather L
HL
Liu
Yuhong
Y
Bolzoni
Elena
E
Jenkins
Shannon C
SC
Wilson
Elizabeth M
EM
Joseph
James D
JD
McDonnell
Donald P
DP
Merry
Diane E
DE
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D020798:Two-Hybrid System Techniques
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D013739:Testosterone; C053541:bicalutamide
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