Nature Neuroscience 9, 907 - 916 (2006)
Published online: 4 June 2006; | doi:10.1038/nn1717
JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transportGerardo Morfini1, 2, 4, Gustavo Pigino1, 4, Györgyi Szebenyi3, Yimei You1, Sarah Pollema1, 2
& Scott T Brady1, 21
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA. 2
Marine Biological Laboratory, Woods Hole, Massachusetts 02543, USA. 3
Basic Neuroscience Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Scott T Brady stbrady@uic.edu 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.
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