Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase

Gerardo A. Morfini, Daryl A. Bosco, Hannah Brown, Rodolfo Gatto, Agnieszka Kaminska, Yuyu Song, Linda Molla, Lisa Baker, M. Natalia Marangoni, Sarah Berth, Ehsan Tavassoli, Carolina Bagnato, Ashutosh Tiwari, Lawrence J. Hayward, Gustavo F. Pigino, D. Martin Watterson, Chun Fang Huang, Gary Banker, Robert H. Brown, Scott T. Brady

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.

Original languageEnglish (US)
Article numbere65235
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - Jun 12 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Morfini, G. A., Bosco, D. A., Brown, H., Gatto, R., Kaminska, A., Song, Y., Molla, L., Baker, L., Marangoni, M. N., Berth, S., Tavassoli, E., Bagnato, C., Tiwari, A., Hayward, L. J., Pigino, G. F., Watterson, D. M., Huang, C. F., Banker, G., Brown, R. H., & Brady, S. T. (2013). Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase. PloS one, 8(6), [e65235]. https://doi.org/10.1371/journal.pone.0065235