JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport.
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.
Morfini
Gerardo
G
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Pigino
Gustavo
G
Szebenyi
Györgyi
G
You
Yimei
Y
Pollema
Sarah
S
Brady
Scott T
ST
D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002458:Cell Fractionation / Q000379:methods; D045744:Cell Line, Tumor; D049832:Decapodiformes / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism; D009447:Neuroblastoma; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
D004791:Enzyme Inhibitors; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D048031:JNK Mitogen-Activated Protein Kinases