Related Experiment Video

Updated: Aug 15, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

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Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded

Diana Piol1,2,3,4, Laura Tosatto4,5, Emanuela Zuccaro1,2,3

  • 1Department of Biomedical Sciences, University of Padova, Padova, Italy.

Science Advances
|January 6, 2023
PubMed

Insights

Spinal and bulbar muscular atrophy involves androgen receptor (AR) phosphorylation. Targeting cell cycle kinases like CDK2 reduces AR phosphorylation, mitigating neurodegeneration in cellular and animal models.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Spinal and bulbar muscular atrophy (SBMA) stems from polyglutamine (polyQ) expansions in the androgen receptor (AR).
  • This leads to toxic gain-of-function, potentially mediated by AR phosphorylation.
  • Understanding AR phosphorylation in SBMA is crucial for therapeutic development.

Purpose of the Study:

  • Investigate kinases and phosphatases targeting polyQ-expanded AR.
  • Determine if polyQ expansions alter AR phosphorylation.
  • Elucidate the role of AR phosphorylation in SBMA neurodegeneration.

Main Methods:

  • Utilized cellular and animal models (flies, mice) of SBMA.
  • Employed mass spectrometry to analyze AR phosphorylation.
  • Conducted small-molecule screening to identify relevant signaling pathways.
  • Performed pharmacologic and genetic manipulation of kinases and phosphatases.

Main Results:

  • PolyQ expansions preserve native AR phosphorylation and increase it at key sites.
  • CDC25/CDK2 signaling enhances AR phosphorylation; calcineurin reduces it.
  • Modulating these pathways affected polyQ-AR function and toxicity in SBMA models.
  • CDK2 ablation decreased brainstem AR phosphorylation and restored gene expression linked to DNA damage and apoptosis.

Conclusions:

  • Cell cycle-regulated kinase CDK2 plays a significant role in SBMA pathogenesis.
  • Targeting CDK2 may offer a therapeutic strategy for SBMA by reducing AR phosphorylation.
  • Findings highlight the importance of AR phosphorylation in neurodegeneration associated with SBMA.

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