Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis

J Biol Chem. 2015 May 15;290(20):12572-84. doi: 10.1074/jbc.M114.617894. Epub 2015 Mar 20.


Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis.

Keywords: aggregation; androgen receptor; neurodegeneration; polyglutamine disease; proteasome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Mice
  • Muscular Disorders, Atrophic / genetics
  • Muscular Disorders, Atrophic / metabolism*
  • Muscular Disorders, Atrophic / pathology
  • PC12 Cells
  • Peptides / genetics
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Proteolysis*
  • Rats
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*


  • Peptides
  • Receptors, Androgen
  • polyglutamine
  • Proteasome Endopeptidase Complex