The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex

Bott, LC (author)

Maric, D (author)

Liu, YH (author)

Merry, D (author)

Fischbeck, KH (author)

(creator_code:org_t)

2016-06-17
2016
English.
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 27703-

Related links:: https://www.nature.c...; show more...; http://kipublication...; https://doi.org/10.1...; show less...

Abstract Subject headings

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/CCdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/CCdh1 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/CCdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA.

By the author/editor: Bott, LC; Salomons, FA; Maric, D; Liu, YH; Merry, D; Fischbeck, KH; show more...; Dantuma, NP; show less...

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