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

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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Figure 1: Effects of PolyQ-AR on kinesin-1 function.
Figure 2: PolyQ-AR alters axonal kinase activities and increases kinesin-1 phosphorylation.
Figure 3: SAPK inhibitors prevent polyQ-AR–induced FAT inhibition.
Figure 4: A SAPK inhibitor reverses inhibitory effects of polyQ-AR on neurite outgrowth.
Figure 5: PolyQ-AR increases JNK activity.
Figure 6: JNK inhibitors prevent both polyQ-AR–induced FAT inhibition and polyQ-AR–induced increase in neurofilament phosphorylation.
Figure 7: Active JNK inhibits FAT and directly phosphorylates KHC.

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Acknowledgements

The authors would like to thank M. McPhaul (UT Southwestern Medical Center, Dallas) for androgen receptor protein; and S. DeBoer and B. Wang for their excellent technical assistance. Research supported by grants from NINDS (NS23868, NS23320, NS41170 and NS43408) to S.T.B. and from ALSA to G.M.

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Correspondence to Scott T Brady.

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Supplementary information

Supplementary Figure 1

Recombinant JNK directly phosphorylates immunoprecipitated endogenous brain kinesin-1 only on KHC. (PDF 3118 kb)

Supplementary Figure 2

Addition of androgen agonist has no effect on FAT with either WT-AR or polyQ-AR. (PDF 838 kb)

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Morfini, G., Pigino, G., Szebenyi, G. et al. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 9, 907–916 (2006). https://doi.org/10.1038/nn1717

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