JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport

Nat Neurosci. 2006 Jul;9(7):907-16. doi: 10.1038/nn1717. Epub 2006 Jun 4.


Expansion of the polyglutamine (polyQ) stretch in the androgen receptor (AR) protein leads to spinal and bulbar muscular atrophy (SBMA), a neurodegenerative disease characterized by lower motor neuron degeneration. The pathogenic mechanisms underlying SBMA remain unknown, but recent experiments show that inhibition of fast axonal transport (FAT) by polyQ-expanded proteins, including polyQ-AR, represents a new cytoplasmic pathogenic lesion. Using pharmacological, biochemical and cell biological experiments, we found a new pathogenic pathway that is affected in SBMA and results in compromised FAT. PolyQ-AR inhibits FAT in a human cell line and in squid axoplasm through a pathway that involves activation of cJun N-terminal kinase (JNK) activity. Active JNK phosphorylated kinesin-1 heavy chains and inhibited kinesin-1 microtubule-binding activity. JNK inhibitors prevented polyQ-AR-mediated inhibition of FAT and reversed suppression of neurite formation by polyQ-AR. We propose that JNK represents a promising target for therapeutic interventions in SBMA.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Axonal Transport / drug effects
  • Axonal Transport / physiology*
  • Blotting, Western / methods
  • Cell Fractionation / methods
  • Cell Line, Tumor
  • Decapodiformes / cytology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Immunohistochemistry / methods
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Microtubules / metabolism
  • Neuroblastoma
  • Peptides / metabolism*
  • Phosphorylation
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Trinucleotide Repeat Expansion*


  • Enzyme Inhibitors
  • Peptides
  • Receptors, Androgen
  • polyglutamine
  • JNK Mitogen-Activated Protein Kinases