2. Academic Validation
  3. Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

  • Sci Adv. 2023 Jan 6;9(1):eade1694. doi: 10.1126/sciadv.ade1694.
Diana Piol 1 2 3 4,  Laura Tosatto 4 5,  Emanuela Zuccaro 1 2 3,  Eric N Anderson 6,  Antonella Falconieri 1,  Maria J Polanco 4,  Caterina Marchioretti 1 2 3,  Federica Lia 1 2 3,  Joseph White 7,  Elisa Bregolin 1 2 3,  Giovanni Minervini 1,  Sara Parodi 8,  Xavier Salvatella 9 10,  Giorgio Arrigoni 1,  Andrea Ballabio 11 12 13 14,  Albert R La Spada 7,  Silvio C E Tosatto 1 15,  Fabio Sambataro 3 16,  Diego L Medina 9 12,  Udai B Pandey 6,  Manuela Basso 17,  Maria Pennuto 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • 2 Veneto Institute of Molecular Medicine (VIMM), Padova, Italy.
  • 3 Padova Neuroscience Center, Padova, Italy.
  • 4 Dulbecco Telethon Institute (DTI), Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • 5 Institute of Biophysics, Consiglio Nazionale delle Ricerche (CNR), Trento, Italy.
  • 6 Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  • 7 Department of Pathology and Laboratory Medicine, Department of Neurology, Department of Biological Chemistry, and the UCI Institute for Neurotherapeutics, University of California, Irvine, CA 92697, USA.
  • 8 Istituto Italiano di Tecnologia, Genova, Italy.
  • 9 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 10 ICREA, Passeig Lluís Companys 23, Barcelona, Spain.
  • 11 Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
  • 12 Department of Medical and Translational Science, Federico II University, Naples, Italy.
  • 13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 14 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 15 Institute of Neuroscience, Consiglio Nazionale delle Ricerche (CNR), Padova, Italy.
  • 16 Department of Neuroscience, University of Padova, Padova, Italy.
  • 17 Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
PMID: 36608116 DOI: 10.1126/sciadv.ade1694
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 Myc and other genes involved in DNA damage, senescence, and Apoptosis, indicating that the cell cycle-regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.

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