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

G Morfini, G Pigino, G Szebenyi, Y You, S Pollema… - Nature …, 2006 - nature.com
G Morfini, G Pigino, G Szebenyi, Y You, S Pollema, ST Brady
Nature neuroscience, 2006nature.com
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 …
Abstract
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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