Antagonistic Effect of Cyclin-Dependent Kinases and a Calcium-Dependent Phosphatase on Polyglutamine-Expanded Androgen Receptor Toxic Gain of Function

Authors

Diana Piol
Laura Tosatto
Emanuela Zuccaro
Eric N Anderson
Antonella Falconieri
Maria J Polanco
Caterina Marchioretti
Federica Lia
Joseph White
Elisa Bregolin
Giovanni Minervini
Sara Parodi
Xavier Salvatella
Giorgio Arrigoni
Andrea Ballabio
Albert R La Spada
Silvio C E Tosatto
Fabio Sambataro
Diego L Medina
Udai B Pandey
Manuela Basso
Maria Pennuto

Publication Date

1-6-2023

Journal

Science Advances

DOI

10.1126/sciadv.ade1694

PMID

36608116

PMCID

PMC9821870

PubMedCentral® Posted Date

1-6-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Receptors, Androgen, Calcium, Gain of Function Mutation, Cyclin-Dependent Kinases, Phosphoric Monoester Hydrolases

Abstract

Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of