The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/CCdh1 ubiquitin ligase complex

• Published in: Scientific reports Vol. 6; no. 1; p. 27703
• Main Authors: Bott, Laura C., Salomons, Florian A., Maric, Dragan, Liu, Yuhong, Merry, Diane, Fischbeck, Kenneth H., Dantuma, Nico P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 17.06.2016
• Subjects: Androgens; Atrophy; Cell cycle; Disease; Ligands; Neuromuscular diseases; Neurons; Proteins; Spinal cord; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27703

Abstract Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/C Cdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/C Cdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/C Cdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA.