Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy

Neuron. 2010 Sep 23;67(6):936-52. doi: 10.1016/j.neuron.2010.08.034.

Abstract

Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary, but not sufficient, for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Animals, Genetically Modified
  • Blindness / genetics
  • Blindness / pathology
  • Cell Line, Transformed
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics
  • Eye / metabolism
  • Eye / pathology
  • Female
  • Furylfuramide / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / genetics
  • Humans
  • Larva / physiology
  • Locomotion / genetics
  • Motor Neurons / metabolism
  • Muscular Disorders, Atrophic / etiology*
  • Muscular Disorders, Atrophic / genetics*
  • Muscular Disorders, Atrophic / pathology
  • Mutagenesis / physiology
  • Mutation / genetics*
  • Neuromuscular Junction / pathology
  • Oligonucleotide Array Sequence Analysis / methods
  • Phenotype
  • Principal Component Analysis
  • Protein Transport / genetics
  • RNA Interference / physiology
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Salivary Glands / metabolism
  • Salivary Glands / pathology
  • Statistics, Nonparametric
  • Transfection / methods
  • Trinucleotide Repeat Expansion
  • Tubulin / metabolism

Substances

  • Actins
  • Drosophila Proteins
  • Receptors, Androgen
  • Tubulin
  • Furylfuramide